Abstract
Notch signaling research dates back to more than one hundred years, beginning with the identification of the Notch mutant in the fruit fly Drosophila melanogaster. Since then, research on Notch and related genes in flies has laid the foundation of what we now know as the Notch signaling pathway. In the 1990s, basic biological and biochemical studies of Notch signaling components in mammalian systems, as well as identification of rare mutations in Notch signaling pathway genes in human patients with rare Mendelian diseases or cancer, increased the significance of this pathway in human biology and medicine. In the 21st century, Drosophila and other genetic model organisms continue to play a leading role in understanding basic Notch biology. Furthermore, these model organisms can be used in a translational manner to study underlying mechanisms of Notch-related human diseases and to investigate the function of novel disease associated genes and variants. In this chapter, we first briefly review the major contributions of Drosophila to Notch signaling research, discussing the similarities and differences between the fly and human pathways. Next, we introduce several biological contexts in Drosophila in which Notch signaling has been extensively characterized. Finally, we discuss a number of genetic diseases caused by mutations in genes in the Notch signaling pathway in humans and we expand on how Drosophila can be used to study rare genetic variants associated with these and novel disorders. By combining modern genomics and state-of-the art technologies, Drosophila research is continuing to reveal exciting biology that sheds light onto mechanisms of disease.
Keywords: Notch signaling, Drosophila, Mendelian Diseases, Functional Genomics, Translational Research
1. Discovery and expansion of the Notch signaling pathway in Drosophila
The first fly Notch (gene symbol: N) mutant was discovered in the laboratory of Thomas Hunt Morgan in 1913, and is named so based on its dominant wing notching phenotype [1,2]. In addition to notched wings, Notch null mutant flies exhibit additional dominant wing vein and mechanosensory bristle density abnormalities, as well as recessive embryonic lethality [3]. This lethality is primarily caused by the conversion of epidermal cells into neurons due to defects in lateral inhibition during neurogenesis, a developmental defect known as the “neurogenic” phenotype [4–7]. The Notch gene was cloned and sequenced in the mid-1980s and was found to encode a large transmembrane receptor-like protein [8,9]. Additional genes that exhibit similar phenotypes when mutated such as Delta (Dl)[10], Serrate (Ser) [11,12], neuralized (neur) [13], mastermind (mam) [14], Hairless (H)[15] and deltex (dx) [16,17] were cloned and characterized around the same time. Additional core genes of the pathway, such as Suppressor o f Hairless [Su(H))][18,19], and genes in the Enhancer o f split-Complex [E(spl)-C, spl is a hypomorphic allele of Notch] [20], were identified through genetic interaction screens with other genes in the pathway and were also cloned in the 1990s[21–26]. Interestingly, epistatic analyses laid the basic outline of the pathway prior to the molecular cloning of many of these genes [27,1], demonstrating the power of pure genetic studies.
Technological advances allowed investigators to look for additional regulators of the pathway that were missed by previous genetic screens. One drawback of classic mutagenesis screens using X-rays and chemical mutagens such as EMS (Ethyl methanesulfonate) is that it is often challenging and labor intensive to map and clone the affected gene and to identify the molecular lesions. Development of transposon (e.g. P-elements, PiggyBac)-based techniques provided a new tool to perform random mutagenesis screens to quickly identify new mutants that exhibit Notch signaling related phenotypes or to molecularly clone previously identified mutants that were left unmapped [28–31].
In Drosophila, embryonic developmental defects can be masked if maternal mRNAs and/or proteins that are deposited into the oocyte by the mother during oogenesis are sufficient for the animals to progress through embryogenesis. Hence, for genes that are abundantly expressed in oocytes, null mutants do not exhibit classical embryomic neurogenic phenotypes but typically die at a later developmental stage and were therefore missed in classic embryonic screens. Such maternal effect genes can be uncovered by generating oocytes that are homozygous for the mutation by combining a FLP (FLiPpase) /FRT (Flippase Recognition Target) system-based site directed mitotic recombination technique [32] with a germline-specific dominant female sterile (DFS) mutation[33,34]. Using this FLP-DFS technique, several novel maternal effect genes were identified [35–37]. In addition, development of reverse genetic strategies based on knowledge of the molecular map of the fly genome allowed to generate mutations in genes that have been implicated in Notch signaling in other systems but have not been studied in Drosophila such as Presenilin (Pns)[38–40]. Finally, additional modifier screens[41–53], somatic mutagenesis screens [54–69], genome-wide or targeted transgenic RNAi (RNA interference) based screens [70–76] and UAS (Upstream Activation Sequence)/GAL4 system [77]-mediated over-expression screens [78–82] have increased our knowledge of genes that regulate Notch signaling in vivo. These genetic screens, along with cell culture based assays[83–86] and systems biology driven approaches including transcriptomics [87–96] and proteomics[97–100] have allowed fly researchers to continue to discover new genes that regulate Notch signaling in diverse contexts. Because diagrams that illustrate Notch signaling now look more like a complicated intertwined web[101] rather than a simple linear pathway[27], the pathway is now occasionally referred to as the “Notch Signaling Network[102,1]” or the “Notch Signaling System[103]” to emphasize the complexity and dynamic nature of the pathway.
2. The Drosophila Notch signaling pathway and its relationship to the mammalian pathway.
Studies of the Notch signaling pathway in Drosophila have provided the framework for subsequent studies in other model organisms, including human[1]. One key advantage of studying Notch signaling in fruit flies is the genetic simplicity of the pathway compared to other organisms. Most core Notch pathway components are encoded by single genes in the fly genome while the structure and function of these factors remain largely conserved between flies and mammals. For example, the Drosophila genome contains one gene (Notch) that encodes for the Notch receptor, whereas the human genome contains four (NOTCH1–4; Table 1)[104]. Even the simple C. elegans genome encodes two Notch receptors [lin-12 (cell LINeage defective-12) and glp-1 (abnormal Germ Line Proliferation-1)][105,106], giving Drosophila an advantage when trying to determine whether certain biological phenomena depend on Notch signaling or when performing structure-function studies of Notch in an in vivo setting [107,108]. In this section, we provide an outline of the Notch signaling pathway as currently understood in Drosophila melanogaster (Fig. 1), while pointing out some key differences found between the fly and mammalian pathways.
Table 1: List of Drosophila genes discussed in this chapter along with their human homologs, disease association and functions.
Human genes in bold have been linked diseases based on OMIM (https://www.omim.org/). The fly genes that are homologous to these genes are also shown in bold. Fly genes with “?” have mammalian homologs that have been shown to be involved in the Notch pathway but their role in Notch signaling in Drosophila have not been studied or are not clear. See [440–449] to find the full list of genes involved in Arp2/3-WASp, ESCRT, AP-3, HOPS and V-ATPase complexes in Drosophila and human.
| Drosophllo gene (symbol) | Human homolog(s) (OMIM disease #) | Protein Functions |
|---|---|---|
| Notch (N) | NOTCH1 (#109730, #616028), NOTCH2 (#102500, #610205), NOTCH3 (#125310, #130720, #615293), N0TCH4 | Receptor |
| Delta (Dl) | DLL1, DLL3 (#277300), DLL4 (#616589) | Ligand |
| Serrate (Ser) | JAG1 (#118450, #187500), JAG2 | |
| rumi | POGLUT1 (#615696,617232) | Receptor glycosylation |
| O-fucosyltransferase 1 (O-fut1) | POFUT1 (#615327) | |
| Shams | GXYLT1, GXYLT2 | |
| fringe | LFNG (#609813), MFNG, RFNG | |
| EGF-domain O-GlcNAc transferase (Eogt) | EOGT (#615297) | |
| neurolized (neur) | NEURL1, NEURL1B | E3 ligase for ligand |
| mind bomb 1(mib1) | MIB1 (#615092) | |
| Furin1 (Fur1)?, Furin2(Fur2)? | FUR | S1 cleavage |
| kuzbanian (kuz) | ADAM10 (#615537) | S2 cleavage |
| Presenilin (Psn) | PSEN1 (#172700, #600274, #607822, #613694, #613737), PSEN2 (#606889, #613697) | S3 cleavage |
| aph-1 | APH1A, APH1B | |
| nicastrin (nct) | NCSTN (#142690) | |
| pen-2 | PSENEN (#613736) | |
| shibire(shi) | DNM1 (#616346), DNM2 (#160150, #606482, #615368), DNM3 | Receptor and ligand endocytosis |
| Sec15 | EXOCS, EXOC6B | Ligand trafficking |
| Rab11 | RAB11A, RAB11B | |
| Arp2/3 Complex: 8 genes (e.g. Arp2, Arp3) [Ref.440] | Arp2/3Complex: 9genes [Ref.445] | |
| WASp | WAS (#301000), WASL | |
| Ehbp1 | EHBP1 (#611868), EHBP1L | |
| temp | PTAR1 | |
| Numb | NUMB, NUMBL | Receptor trafficking |
| Sanpodo (Spdo) | - | |
| deltex (dx) | DTX1, DTX2, DTX3, DTX3L, DTX4 | |
| supressor of deltex (su(dx)) | ITCH (#613385), WWP1, WWP2 | |
| lethal(2)giant discs 1 (l(2)gd1) | CC2D1A (#608443), CC2D1B | |
| ESCRT complex: 20 genes (e.g. shrub, Vps25) [Ref.441] | ESCRT complex: 30 genes (#114480, #600795, #605387, #614898, #614696) [Ref.446] | |
| AP-3 complex: 4 genes (e.g. carmine (cm), ruby(rb))[Ref.442] | AP-3 complex: 7 genes (#608233, #617050, #617276)) [Ref.447] | |
| HOPS complex: 7 genes (e.g. carnation (car), deep orange (dor)) [Ref .443] | HOPS complex: 8 genes (#208085, #616683, #617303) [Ref.448] | |
| V-ATPase complex: 33 genes (e.g. VhaAC39–1, Vha68–2) [Ref.444] | V-ATPase complex: 23 genes (#124480, #219200, #259700, #267300, #278250, #259700, #616455, #617402, #617403) [Ref .449] | Vesicle acidification |
| Supressor of Hairless (Su(H)) | RBPJ (#614814) | Transcription factor |
| Hairless (H) | - | Corepressor |
| - | SPEN (SHARP/Mint) | |
| - | FHL1 (KyoT2) (#300695, #300696, #300717, #300718) | |
| groucho(gro) | TLE1, TLE2, TLE3, TLE4, TIE5, TLE6 (#616814) | |
| C-terminal Binding Protein (CtBP) | CTBP1, CTBP2 | |
| mastermind (mam) | MAML1, MAML2, MAML3 | Coactivator |
| nejire(nej) | EP300 (#114500, #613684), CREBBP (#180849) | |
| Enhancer of split complex [E(spl)-C): 7 bHLH repressor genes: e.g. E(spl)-m8) | HES1, HES2, HES3, HES4, HES5, HES6, HES7 (#613686) | Target Genes |
| sage? | MESP2 (#608681) | |
| Doc?1, Doc2?, Doc3? | TBX6 (#122600) | |
| Cdk8? | CDK8 | NICD degradation |
| archipelago (ago)? | FBXW7 |
Figure 1: Schematic diagram of the Drosophila Notch signaling pathway.
Canonical Notch signaling takes place between two juxtaposed cells (left: signal sending cell, right: signal receiving cell). Different steps of signal activation and functions of molecules depicted here are described in detail in the main text. Note that some players depicted here only regulate Notch signaling in specific contexts. Abbreviations for proteins shown are based on FlyBase gene symbol nomenclature (also see Table 1).
2.1. Biosynthesis and trafficking of the Notch receptor
For Notch signaling to be activated in a canonical fashion, two cells, one signal receiving and one signal sending, need to be juxtaposed (juxtacrine signaling). The Notch receptor is synthesized in the signal receiving cell and undergoes a number of post-translational modifications (PTMs) in both the endoplasmic reticulum (ER) and the Golgi apparatus[109]. In the ER, the extracellular domain of Notch becomes heavily O-glucosylated by Rumi (protein O-glucosyltransferase)[54] and O-fucosylated by O-fut1 (protein O-fucosyltransferase)[110,35]. The monosaccharides added by these enzymes to selective EGF (epidermal growth factor)-like repeats of Notch can further be elongated by Shams (glucoside xylosyltransferase)[111,112] and Fringe (Fng, O-Fucosylpeptide β3-N-acetylglucosaminyltransferase)[113–115,29] in the ER or Golgi apparatus. Experiments using enzymatically inactive mutants and transgenic over-expression strains have revealed that glycosylation of Notch is critical for ligand selectivity as well as for proper signal activation upon ligand-receptor interaction[116,117]. Both Drosophila and mammalian Notch receptors have also been shown to undergo additional glycosylation by Eogt [EGF-domain O-GlcNAc (N-Acetylglucosamine) transferase] in the ER[118,119]. Eogt mutant flies do not exhibit obvious Notch signaling defects but genetically interact with other members of the pathway, indicating that this gene plays a modulatory role.
In addition, Notch undergoes the first (S1) proteolytic cleavage mediated by an unknown (potentially a furin-like) protease, in the Golgi. It has been reported that in Drosophila cells the majority of the Notch receptor found at the cell membrane consists of the ~300 kDa full-length protein[120,121] while in mammals, most Notch at the cell surface has undergone S1 cleavage [122,123]. Although there has been some controversy in the Drosophila literature [124], S1 cleavage is not absolutely required for signal activation but rather it seems to facilitate the transport of the receptor to the cell surface contributing to signal strength[125], similar to the effect of S1 cleavage on mammalian Notch receptors [126].
2.2. Biosynthesis and trafficking of the ligands and ligand-receptor interaction
Notch receptors that have undergone proper PTMs in the ER and Golgi are exported to the plasma membrane where they can physically interact with ligands presented by the neighboring signal-sending cells. While the Notch receptor is expressed relatively broadly[127,128], the ligands Delta[129–133] and Serrate[11,12,134] exhibit unique and dynamic patterns of expressions during development. Together with the selective expression of Fng[29], which facilitates Notch-Delta interactions while suppressing Notch-Serrate interactions[135,114], the spatial and temporal pattern of ligand expression plays a critical role in determining where Notch signaling becomes activated. In mammals, three orthologs of Delta [Delta-like (DLL)1,3,4] and two orthologs of Serrate [Jagged (JAG) 1,2] are present. The existence of multiple DLL and JAG ligands, together with the presence of three fng orthologs (Lunatic (LFNG), Manic (MFNG) and Radical (RFNG) Fringe), increases the complexity of Notch signaling in mammals compared to Drosophila[104]. Multiple ligands can be expressed in the same tissue and can bind/activate the four Notch receptors with varying affinities. Furthermore, DLL3, the most divergent of the DLL paralogs, functions as a decoy ligand due to the lack of monoubiquitination sites in the cytoplasmic domain required for receptor activation[136]. Hence, this protein has been proposed to inhibit rather than activate Notch signaling in a cell autonomous manner by binding to the Notch receptors in cis (cis-inhibition) and preventing them from binding to ligands presented in trans[137]. Interestingly, three mammalian orthologs of fng have recently been shown to modify the same Notch receptor in different manners; some modifications can inhibit certain ligand-receptor interactions, others can potentiate them[138]. Hence, four receptors × five (four primarily activating and one inhibiting) ligands × 3 Fng enzymes generates a much more complicated scenario in mammals, compared to the one receptor × two (primarily activating) ligands × one Fng enzyme system in Drosophila.
Ligand-receptor interaction is necessary but not sufficient for canonical Notch signaling activation. After ligand and receptor bind to each another, the signal sending cell endocytoses the ligand, generating a physical force that unravels a second (S2) cleavage site embedded in the negative regulatory region (NRR) of the Notch receptor. Without the pulling force, three LNR (Lin-12/Notch Repeat) domains within the NRR limit the access of ADAM (A Disintegrin and Metalloprotease) proteases and prevent them from cleaving the S2 site[139,140]. Upon the conformational change mediated by ligand-endocytosis and force generation, Kuzbanian (Kuz, ADAM10 in human) cleaves the S2 site, shedding the majority of the extracellular domain and leaving behind a membrane-tethered portion of the Notch receptor referred to as the NEXT (Notch extracellular truncation)[141]. In order to endocytose the ligands and generate the pulling force, cytoplasmic domains of Delta or Serrate must be mono-ubiquitinated by E3 ubiquitin ligases Neuralized (Neur) or Mindbomb 1 (Mib1)[142,143]. neur and mib1 are differentially expressed and function in different Notch dependent biological processes during Drosophila development[144–149].
Although mind bomb 2 (mib2, MIB2 in human) is present in the fly genome[150], its in vivo role in Notch signaling is not clear [151]. The human genome contains two neur orthologs (NEURL1, NEURL1B) and one mib1 ortholog (MIB1). Although studies based on cultured cells indicate that these genes can all regulate Notch activity[152–154], only Mib1 has been reported to exhibit a strong Notch signaling defect in vivo when mutated in mice [155]. Hence, the dependence of the Notch pathway on ligand mono-ubiquitination by Neur and Mib family proteins seems to have diverged and/or acquired a high degree of redundancy during evolution.
2.3. Proteolytic cleavages of the Notch receptor and transcriptional regulation
After S2 cleavage of Notch, NEXT is further processed by the γ-secretase complex, an intramembrane protease composed of Presenilin (Psn), Nicastrin (Nct), Anterior pharynx defective 1 (Aph-1), and Presenilin enhancer-2 (Pen-2). Two Psn orthologs (PSEN1 and PSEN2) and two aph-1 orthologs (APH1A and APH1B) together with single orthologs for Nct (NCSTN) and pen-2 (PSENEN) exist in the human genome. γ-secretase performs the S3 cleavage of NEXT to release the Notch intracellular domain (NICD) from the membrane [156]. It remains unclear whether γ-secretase primarily processes NEXT at the cell membrane, within endocytic vesicles or both. The requirement of the genes that primarily function in Clathrin-dependent endocytosis [e.g. by Dynamin encoded by the shi (shibire) gene] for Notch activation in signal-receiving cells in certain contexts supports that S3 cleavage takes place in endocytic vesicles[157,158]. However, other studies argue that S3 cleavage primarily occurs at the plasma membrane and that endocytosis is not required[159], suggesting that this may be a context-specific issue. Indeed, proteins and molecular machineries that regulate endocytic trafficking and degradation of Notch receptors such as Dx (E3 ligase)[160,161,53], Suppressor of dx [Su(dx), E3 ligase] [162,163], ESCRT (Endosomal Sorting Complexes Required for Transport) complex (multivesicular body formation) [62,164], Lethal (2) giant discs 1 [L(2)gd1, adaptor protein?][165,166], AP-3 (Adaptor Protein-3) complex (late endosomal trafficking) and HOPS (HOmotypic fusion and Protein Sorting, endosome-lysosome fusion) complexes[167,168] and Vacuolar-ATPase (V-ATPase, vesicle acidification) complex [65,169] can fine-tune Notch activity, likely by regulating the efficiency of Notch cleavage in different subcellular compartments and/or modulating the balance between ligand-dependent and -independent signaling activities[170,171].
After being released from the membrane, NICD trafficks to the nucleus and forms a transcriptional activation complex with Su(H) [RBPJ (Recombination signal Binding Protein for immunoglobulin kappa J region) in human] [172,173,18] and Mam [MAML (Mastermind-like)1–3 in human] [174,175]. In the absence of NICD, Su(H) is bound to the co-repressor Hairless (H)[176,15,177] which in turn recruits additional co-repressors such as Groucho [TLE (Transducin-like enhancer protein) 1–6 in human, TLE5 is also referred to as AES (Amino-terminal Enhancer Of Split)] and CtBP (C-terminal Binding Protein, CTBP1–2 in human) to silence target genes [178–182]. Once NICD enters the nucleus and binds to Su(H), H is no longer able to bind to Su(H)[183]. The active NICD-Su(H)-Mam complex further recruits transcriptional co-activators such as the histone acetyltransferase CBP [CREB (cAMP response element binding protein)-binding protein]/p300 [nejire (nej) in Drosophila, EP300 (E1A binding protein P300) and CREBBP (CREB-binding protein) in human] to initiate transcription of downstream target genes [71,184]. While most genes that are involved in the transcriptional activation complex are conserved between flies and mammals, no direct homolog of Hairless exists in mammalian genomes. Instead, two structurally unrelated co-repressors, KyoT2 (encoded by the FHL1 gene in human)[185] and SHARP [SMRT/HDAC1 Associated Repressor Protein, encoded by the SPEN (SPlit ENds family transcriptional repressor) gene in human, also called Mint] [186,187] play the same function, binding to RBPJ and further recruiting additional corepressors to silence transcription[188]. Interestingly, Hairless and KyoT2/SHARP bind to RBPJ through different molecular mechanisms[183,189,190], suggesting that these genes were integrated into the Notch pathway independently through convergent evolution.
A number of Notch target genes have been identified to date[191], but the best characterized target genes are found in the E(spl)-C[177,192–194]. E(spl)-C encodes seven basic helix-loop-helix (bHLH) proteins that function as transcriptional repressors (E(spl)-m3, m5, m7, m8, mβ, mγ, mδ)[195–198]. In addition, the gene that encodes Gro as well as four Bearded family proteins (E(spl)-m2, m4, m6, mα), a group of small proteins that inhibit Neur function, are also found at this locus[199–202]. bHLH E(spl) proteins antagonize the activity of proneural bHLH proteins such as Achaete and Scute during neurogenesis and this relationship is generally conserved in mammals [203–206]. Homologs of bHLH E(spl) genes are known as HES (Hairy and Enhancer o f Split) genes in mammals (HES1–7 human)[207,208]. Together with the structurally and evolutionarily related HEY (Hairy/Enhancer-of-split related with YRPW motif protein) genes (HEY1, HEY2, HEYL in human) which are also under the control of Notch signaling in many contexts [209,210], these factors play critical roles in developmental events that involve proneural transcription factors as well as in a number of other Notch-dependent contexts [211,212].
Finally, signal termination of Notch is mediated by ubiquitin-proteasomal degradation of the NICD. Based on experiments in mammalian systems, the PEST [proline (P), glutamic acid (E), serine (S) and threonine (T)-rich] domain near the C-terminus of NICD is required for phosphorylation by CDK8 (Cyclin-dependent kinase 8) and subsequent poly-ubiquitination by the ubiquitin E3 ligase FBXW7 (F-BoX and WD repeat domain containing) 7. However, whether Cdk8 and archipelago (ago, FBXW7 homolog) also play similar roles in the Drosophila Notch signaling pathway in vivo waits further confirmation.
2.4. Non-canonical activation of the pathway and additional facts to note
In addition to the canonical signaling pathway described above, a number of studies have revealed non-canonical ways by which Notch signal can be activated (e.g. non-canonical ligands, Su(H)-independent signaling, signal crosstalk). Due to space limitations, we will not discuss these alternative pathways here and refer the readers to the following review articles[213–217].
As we have seen, there are a number of similarities between the Drosophila and human (mammalian) Notch signaling pathways but there are a number of differences we referred to that one should keep in mind. As we have already discussed, duplication (JAG1/2), triplication (DLL1/3/4 and LFNG/MFNG/RFNG) and quadruplication (NOTCH1–4) of core genes in the pathway during mammalian evolution have increased the complexity of the pathway compared to Drosophila. Some genes maintained redundancy while others acquired novel functions or became subfunctionalized to fine-tune the pathway in mammals. In addition, there have been new genes that have been incorporated into the pathway, some of which do not have an obvious ortholog in Drosophila (e.g. KyoT2, SHARP). In addition, one should also keep in mind that there are other key biological differences (e.g. minimal role of CpG DNA methylation in gene regulation in Drosophila[218,219], lack of primary cilia in most somatic cells[220,221]) that are known to exist between insects and mammals and that may impact the translation of some findings from Drosophila to human.
3. Notch signaling in Drosophila development
Since the identification of Notch and other members of the canonical signaling pathway as fundamental genes involved in the embryonic and post-embryonic development of Drosophila, numerous studies have focused on elucidating the role of Notch signaling during the development of diverse organs in the fly[222,223]. Over the years, several tissues that exhibit characteristic morphological defects when Notch signaling activity is altered have been used as models to understand how the pathway works and to further identify novel pathway members. These include the embryonic central nervous system (brain and ventral nerve cord), the adult peripheral nervous system (mechanosensory bristles, chordotonal organs and eyes), adult appendages (wings and legs), hematopoietic organs (lymph gland) and reproductive organs (ovary and testis). In addition, studies on post-developmental functions of Notch signaling, such as its role in synaptic plasiticity [224,225] and stem cell maintenance/differentiation[226–228], are also being explored. Here, we will focus on the role of Notch signaling during the development of the adult mechanosensory organs (bristles) and the wing margin during Drosophila development. These two tissues are well established model systems to study three conceptually distinct modes of Notch signaling that are reiteratively used during morphogenesis and organogenesis across evolution: lateral inhibition, lineage decisions and inductive signaling[223,229–231].
3.1. Notch signal-mediated lateral inhibition during early development of mechanosensory bristles
Mechanosensory bristles are part of the peripheral nervous system that allow the fly to sense mechanical forces and provide proprioception for coordinated movement and behavior (Fig. 2A–B)[232,233]. The bristles in the notum (dorsal thorax) are formed in a highly reproducible and stereotypical fashion[229] and their development can be easily traced using fixed or live imaging strategies [234]. Bristle precursor cells, which are called sensory organ precursor (SOP) cells, are selected out from a group of cells referred to as the proneural cluster (Fig. 2C). Proneural clusters are specific groups of ectodermal cells that begin to express proneural bHLH transcription factors of the Achaete-Scute Complex (AS-C, ASCL1–5 in human[235]). A single SOP is selected from a proneural cluster through Notch-mediated lateral inhibition [230]. Lateral inhibition is achieved through a genetic circuitry that works through a feedback loop that involves inductive and repressive transcriptional relationships between Notch signaling components and several transcription factors (Fig. 2D)[109,236,204]. In a proneural cluster, all cells initially express both Notch and Delta and have equal potential to either become an SOP or an epithelial cell. Delta activates Notch in neighboring cells, which leads to expression of downstream target genes in the E(spl)-C. E(spl) proteins function as transcriptional repressors and down-regulate the expression of AS-C, which are positive regulators of Delta transcription. Thus, decrease in AS-C expression due to upregulation of E(spl) leads to the reduction of Delta expression in the signal-receiving cell.
Figure 2: Notch signaling is required for lateral inhibition and lineage decisions during mechanosensory organ development.
A) Photograph of the fly notum. Large (macrochaetae) and small (microchaetae) are organized in a stereotypical fashion. B) Schematic diagram of a single mechanosensory organ (bristle). C) Schematic diagram representing the development of a single bristle. “N” indicates cells that activate Notch signaling. D-D’) Schematic diagrams of lateral inhibition during the selection of a sensory organ precursor (SOP) cell. In the beginning both cells have the potential to become an SOP. As development progresses, two cells acquire distinct fates through amplification of small differences through transcriptional feedback loops built into the stem. Cells that become the net signal sending cell becomes the SOP (labeled in red), and the net signal receiving cell(s) takes the epithelial cell fate. Panels B and C were adapted and mofidied from [108].
In addition to inducing the expression of Delta, AS-C bHLH transcription factors positively regulate the expression of a zinc finger nuclear protein called Senseless (Sens) [GFI1 (Growth Factor Independent 1 transcriptional repressor) in human] [237–239]. Sens participates in this genetic circuitry by promoting the transcription of AS-C target genes by working as a transcriptional coactivator through physical interactions with AS-C bHLH proteins. In addition, at low expression levels Sens functions as a transcriptional repressor through direct binding to DNA, thus acting as a binary switch to further amplify the feedback loop that is established by AS-C, Delta and E(spl)[238]. Within the young proneural cluster, the expression level of AS-C, Sens and Notch signaling components are similar among the cells. However, at some time point during development, the equilibrium of Notch-Delta signaling becomes disrupted which is thought to be through a stochastic event[240–242]. When one cell receives less Notch signal, expression of E(spl) within this cell is reduced and Delta expression becomes derepressed. Thus, cells receiving less Notch signal begin to express higher levels of Delta, which in turn can send stronger Delta mediated Notch signals to neighboring cells. Through this feed-forward loop, one cell that continues to send the signal to neighboring cell eventually becomes selected out as the SOP (low Notch activity), while the other cells remain in the epithelial cell fate [high Notch activity, (Fig. 2C–D)]. This mechanism allows the bristles on the fly notum to be formed in an evenly spaced manner. Loss of Notch signaling during this process, which occurs between 0 to 14 hours after puparium formation (hAPF), leads to generation of more SOPs at the expense of epithelial cells (Fig. 3A–B)[230]. During lateral inhibition of the SOPs, only Notch-Delta signaling is essential and Notch-Serrate signaling does not seem to be required[108,243]. Thus, the loss of Serrate does not show any defect in bristle spacing, whereas the loss of Delta in mutant clones exhibits bristle tufting in the adult notum[244].
Figure 3: Phenotypic consequences of Notch signaling loss during mechanosensory organ development.
A) Notch signaling mediates the lateral inhibition to specify an SOP from a proneural cluster. Cells that receive high Notch signaling becomes epidermal cells. B) Upon loss of Notch signaling during lateral inhibition, all cells takes the SOP cell fate. Photographs show SOPs marked by Senseless expression (Red). C) Reiterative Notch signaling is required to specify the four cell fates of the mechanosensory organ. The cells that receives the highest amount of Notch signaling becomes the Socket cells while the cells that receive the least becomes the neuron. D) Upon loss of Notch signaling during lineage decisions all cells take on the neuronal fate. Photographs show neuronal nuclei and membrane, labeled by antibodies against Elav (Red) and Hrp (Green). Panels A and B were adapted and mofidied from [108].
3.2. Notch signaling-mediated lineage/cell fate decisions upon asymmetric cell division of sensory organ precursor cells
Each bristle is composed of four cells: a socket, a shaft, a sheath and a mechanosensory neuron. These four cells are generated by a series of asymmetric cell divisions of the SOP and subsequent lineage specification through Notch signaling (Fig. 2B–C) [245,246]. Socket and shaft cells are located externally and provide the mechanical apparatus for mechanosensation. The neuron and the sheath cell, which is thought to function as a glial cell, are located internally and cannot be observed by simple visual examination of the fly notum. The dendrite of the mechanosensory neuron is located at the base of the bristle and is thought to contain mechanosensitive ion channels that open to depolarize the neuron upon deflection of the shaft cell [247]. The axon of the neuron targets the central nervous system to transmit the signal to higher nervous system centers [248].
The SOP, also referred to as the pI cell in this context, first divides along the anterior-posterior axis of the body to give rise to the posterior pIIa cell, the precursor cell of the external cells, and the anterior pIIb cell which gives rise to the internal cells (Fig. 2C). When the SOP divides, the cell fate determinants Neur and Numb are segregated into the pIIb cell but not into the pIIa cell [249,250]. This unequal inheritance of cell fate determinants, mediated by the Par3 (encoded by the bazooka gene in Drosophila)-Par6-aPKC (atypical Protein Kinase C) complex, determines the subsequent direction of Notch signaling between the pIIa and pIIb cells in order to specify distinct fates. Both pIIa and pIIb express comparable levels of Notch, Delta and Serrate but Neur, essential for ligand activity by promoting their mono-ubiquitination and endocytosis, is apportioned to the pIIb cell. Hence, ligands in the pIIb cell have the ability to signal, whereas ligands in the pIIa cell do not[249]. In addition, Numb (NUMB and NUMBL in human), an endocytic adaptor protein, acts in the pIIb cell to block signal reception by promoting the endocytosis of Notch and Sanpodo (Spdo)[251,67,252]. Spdo encodes a transmembrane protein required for cell fate specification at the cell surface by further modulating the trafficking of the Notch receptor [253]. Unlike Numb, Spdo has no obvious human homolog. Furthermore, proteins that regulate the proper trafficking of the ligands to the apical signaling interface, such as Sec15 (Secretory 15, component of the Exocyst complex)[55], Rab11 (small GTPase involved in vesicle recycling and exocytosis)[254], EHBP-1 [EH (Eps15 Homology) domain Binding Protein-1, adaptor protein that binds to Sec15 and Rab11) [60], Tempura (geranylgeranyltransferase for certain Rabs including Rab11)[58] and the Arp (Actin-related protein) 2/3-WASp (Wiskott-Aldrich Syndrome protein) complex (regulator of cytoskeleton and vesicle trafficking through Actin polymerization) [56,255] are also critical for proper communication between the two cells. Together, these mechanisms create a bias so that the pIIb cell becomes the signal-sending cell while the pIIa cell becomes the signal-receiving cell.
The pIIa and pIIb cells further undergo several rounds of asymmetric cell divisions and signaling to specify the four distinct cell types. An additional glial cell is formed through asymmetric division of the pIIb cell but this cell undergoes apoptosis and does not contribute to the mechanosensory organ in the adult notum [256,257]. A complete loss of Notch signaling during this process, which occurs between 16 to 24 hAPF, leads to a neurogenic phenotype (Fig. 3C–D)[230]. As a result, external socket and shaft cells, as well as the internal sheath cells, are lost leading to a balding phenotype on the notum. In contrast, gain of Notch signaling during this process leads to generation of more external cells at the expense of internal cells, thus exhibiting a multiple socket cell phenotype in the most extreme case [258]. The two ligands, Delta and Serrate, act redundantly during linage decisions to form the bristle. The loss of function of either ligand alone does not show lineage specification defects but cells mutant for both ligands exhibit a strong balding defect similar to loss of Notch[243]. In summary, Notch is used for both lateral inhibition and cell fate specification during the development of the mechanosensory organ, and is regulated by a number of distinct factors.
3.3. Notch mediated inductive signaling during the formation of the wing margin
The wing of a fly is a bilayered structure composed of dorsal and ventral wing blades that are bound together via integrin mediated attachment (Fig. 4A–B)[259]. The two surfaces of the wing blade meet at the wing margin to form the rim of the wing. Mechanosensory and chemosensory bristles are located along the anterior wing margin, whereas noninnervated bristles align the posterior wing margin. The wing margin is formed during the larval stage within the wing imaginal disc, which gives rise to the future wing and notum tissue of the adult fly. The dorsal domain of the wing imaginal disc expresses the selector gene apterous, which encodes a homeodomain transcription factor with two LIM (Lin11, Isl-1 and Mec-3) domains[260]. Apterous turns on the expression of Serrate and Fng specifically in the dorsal domain, whereas Notch and Delta are expressed in both compartments[261–263]. Serrate can signal to the ventral compartment but cannot signal within the dorsal compartment due to differences in Fng modification of Notch in the two compartments [264,265,114,266,267]. Conversely, Delta can signal to the dorsal cells but cannot signal to the ventral compartment[114,266,268]. This bidirectional signaling through Delta and Serrate along the dorsal-ventral boundary leads to the activation of Notch, which in turn activates genes specific for the wing margin such as wingless (wg) and cut (Fig. 3C)[269–271,262,272]. Wg (WNT1 in human), a Wnt signaling ligand, acts as a morphogen to pattern the wing along the dorsal-ventral axis[273,272,274] whereas Cut is a homeodomain transcription factor that is involved in maintaining the expression of Wg as well as repressing the expression of Delta and Serrate within the future wing margin tissue [275,276,270]. At later stages in wing margin development, the cells that coexpress Wg and Cut down-regulate the expression of Notch ligands, whereas cells flanking the wing margin cells express high levels of Delta and Serrate via high Wnt signaling activation. Thus, Delta and Serrate from the flanking cells continue to signal to the wing margin cells to maintain the expression of Wg and Cut, reinforcing the establishment of a solid compartmental boundary through a positive feedback loop[277,276]. Loss of Notch signaling during this induction leads to the loss of wing margin tissue (Figure 4D–E). Unlike decisions in the bristle lineage where Delta and Serrate act redundantly, both ligands are necessary for wing margin specification. Hence, loss of either Delta or Serrate alone leads to a reduction in Wg and Cut expression, resulting in the notching of the wing[267]. Mild loss of wing margin tissue at the distal tip of the wing can even be seen in flies that are heterozygous for a null mutation of Notch [3]. This haploinsufficiency phenotype of Notch, which originally gave the name “Notch” to the gene and the pathway, emphasizes the strict dosage sensitivity of inductive signaling during wing margin formation.
Figure 4: Notch signaling is required for inductive signaling during wing margin development.
A) Photograph of a DAPI-stained wing imaginal disc that is pseudocolored for the dorsal domain (green) and the future wing margin (red). B) Schematic diagram of a transverse section of a part of the fly thorax. The dorsal wing imaginal disc (green) gives rise to the notum (dorsal thorax) and the dorsal wing blade. The ventral wing imaginal disc forms the ventral wing blade. The boundary between the dorsal and ventral compartment becomes the wing margin (red). C) Notch mediated inductive signaling specifies the future wing margin during imaginal disc development. Serrate (Ser) signals from the dorsal to the ventral compartment (red arrows) whereas Delta (Dl) signals from the ventral to the dorsal compartment (yellow). D) Upon Notch signaling activation at the dorsal-ventral boundary, genes such as Wingless (red) and Cut (not shown) are expressed, specifying the wing margin. E) Upon loss of Notch signaling during inductive signaling, these genes fail to be expressed and the wings exhibit a “notching” phenotype. Abbreviation of axes in panels A-B: D (Dorsal), V (Ventral), A (Anterior), P(Posterior), M (Medial), L (Lateral). Panel C was adapted and mofidied from [108].
4). Human diseases caused by rare mutations in Notch pathway genes
In parallel to efforts to reveal the genes and mechanisms that coordinate the Notch signaling pathway using model organisms and cultured cell lines, medical research has uncovered a strong link between Notch and many human diseases[278–283]. To date, inherited or de novo mutations in human genes that encode core components of the pathway such as the receptors, ligands, transcription factors and downstream target genes have been shown to cause diverse Mendelian disorders[284,285]. By studying these rare diseases and patients from a clinical perspective, physicians and scientists made discoveries that had major impacts on basic Notch research. In addition, there is growing evidence that misregulation of Notch signaling may participate in more common disorders, ranging from neuropsychiatric to metabolic disorders [286–289]. Furthermore, somatic mutations in genes in the pathway and/or misregulation of Notch signaling activity has also been linked to oncogenesis and tumor progression in different cancer types[290,141,291]. Here, we will provide an overview of Mendelian disorders caused by mutations in genes that encode core Notch signaling components in human, most of which are catalogued in Online Mendelian Inheritance in Man (OMIM)[292], an online database of human genotypes and phenotypes. The role of Notch signaling in cancer will be further discussed in other chapters of this book (e.g. Chapters 9, 15 and 18).
4.1. Adams-Oliver syndrome
Adams-Oliver syndrome (AOS) is a developmental disorder characterized by aplasia cutis congenital (a congenital skin defect, typically of the scalp) and transverse limb defects (typically digital amputations) [293,294]. In addition, some AOS patients exhibit nervous system and cardiac/vascular abnormalities. Dominant mutations in NOTCH1 (OMIM #616028), DLL4 (OMIM #616589), RBPJ (OMIM #614814) and recessive mutations in EOGT (OMIM #615297) are known to cause this condition. Additional mutations in DOCK6 [Dedicator O f CytoKinesis 6, guanine nucleotide exchange factor (GEF) for Rho-GTPases, OMIM #614219] and ARHGAP31 [RHo GTPase Activating Protein 31, GTPase-activating protein (GAP) for Rho-GTPases, OMIM #100300] have also been linked to AOS but the relationship between these genes and Notch signaling is currently unknown. A number of missense, nonsense and frameshift mutations in NOTCH1 [295,296] and DLL4[297] have been found in patients with this condition, suggesting that haploinsufficiency is the underlying mechanism of the dominant inheritance for these genes. AOS-linked mutations identified in RBPJ have been shown to impair the DNA binding capacity of the encoded protein[298].
4.2. Alagille syndrome and Hajdu-Cheney syndrome
Alagille Syndrome is a developmental disorder that affects a number of organ systems including the liver (paucity of intrahepatic bile ducts), cardiovascular system (stenosis of the pulmonic valve), kidney (renal dysplasia), skeleton (abnormal “butterfly” vertebrae), eye (posterior embryotoxon, a characteristic defect in the layers of the eye called the ring of Schwalbe) and dysmorphic facial features [299]. The main manifestation of disease is seen in the liver where bile duct formation is defective, resulting in chronic cholestasis [300]. Dominant nonsense, frameshift and missense mutations in JAG1 (~90% of cases, OMIM #118450)[301,302] or NOTCH2 (a few % of cases, OMIM #610205)[303] cause this condition, suggesting that haploinsufficiency of these genes is the underlying genetic mechanism. Dominant mutations in NOTCH2 are also associated with a different congenital disease called Hajdu-Cheney syndrome that primarily manifests as a skeletal disease (OMIM #102500) [304–306]. Mutations identified in this disease are late truncating mutations that remove the C-terminal PEST domain of NOTCH2, which likely acts as gain-of-function alleles by increasing its stability. Hence, both loss- and gain-of-function mutations in NOTCH2 cause rare genetic disorders that are phenotypically and mechanistically distinct from each other.
4.3. Aortic Valve Diseases and Tetralogy of Fallot
Notch signaling plays a key role during the development of the cardiovascular system[280]. Notch is used reiteratively in cardiac development: during cardiomyocyte specification and differentiation, atrioventricular canal development, cardiac valve development, ventricular trabeculation, and outflow tract development. Cardiac defects are often seen in patients with AOS, Alagille Syndrome and Hajdu-Cheney syndrome with a number of different cardiac lesions. Dominant mutations in NOTCH1 and JAG1 have also been linked to primary congenital heart diseases such as Aortic Valve Disease 1 (OMIM #109730)[307,308] and Tetralogy of Fallot (OMIM #187500)[309], respectively. NOTCH1 mutations linked to Aortic Valve Disease are nonsense and frameshift mutations, suggesting a haploinsufficient mechanism [310]. Why some patients with loss-of-function mutations in NOTCH1 exhibit Adams-Oliver syndrome while others only present cardiac symptoms is unclear. To date, all mutations in JAG1 that are linked to Tetralogy of Fallot are missense alleles[309,311–313], which may have different consequences from the Alagille syndrome-linked mutations in this gene. In addition, dominant mutations (one nonsense and one missense, respectively) in MIB1 (OMIM #615092)[314] and MIB2 (OMIM #N/A)[315] have been linked to Left Ventricular Noncompaction (LVNC), a form of cardiomyopathy. Patients with a mutation in MIB2 also exhibit gastrointestinal phenotypes and have been classified as Ménétrier disease [315]. In sum, cardiac defects are often associated with mutations affecting Notch signaling, which is likely due to the fact that Notch signaling plays a number of critical roles during cardiovascular development in vertebrates [316]. These phenotypes can be presented together with defects in other organ systems, reflecting the highly pleiotropic nature of this pathway.
4.4. Spondylocostal Dysostosis
Notch signaling also affects skeletal development, and mutations in several core signaling components and downstream target genes have been associated with rare skeletal disorders[317,318]. Spondylocostal Dysostosis (SCDO) is primarily an autosomal recessive disorder, presenting with abnormal vertebra formation and patterning defects. Five of the six types of SCDO identified to date are caused by recessive mutations in core Notch signaling pathway components and downstream target genes: SCDO1; DLL3 (OMIM #277300)[319], SCDO2; MESP2 (Mesoderm posterior bHLH transcription factor 2, Notch target gene, OMIM #608681)[320], SCDO3; LFNG (OMIM #609813)[321], SCDO4; HES7 (Notch target gene, OMIM #613686)[322], and SCDO5; TBX6 (T-box 6, Notch target gene [323,324], OMIM #122600, autosomal dominant forms have also been reported)[325,326]. The sixth SCDO gene, RIPPLY2 (Ripply transcriptional repressor 2, OMIM #616566), lies downstream of the pathway and regulates the expression and/or function ofMESP2 and TBX6[327]. In mice, many of these genes have been shown to play a critical role in somitogenesis [328,329], indicating that SCDO is caused by misregulation of an evolutionarily conserved transcriptional pathway that regulates somite (precursor of vertebra and other tissues) formation[330,331].
4.5. CADASIL and NOTCH3-related disorders
Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is the most common heritable cause of stroke and vascular dementia, characterized by five main symptoms: migraine with aura, subcortical ischemia, mood disorders, apathy, and cognitive decline generally found in families with an autosomal dominant pattern of inheritance [332]. Accumulation of granular osmophilic material (GOM), which accompanies vascular smooth muscle degeneration and arteriopathy in postmortem CADASIL patient brain tissue, is a characteristic pathological feature of the disease[333]. Over 90% of CADASIL patients carry a dominant mutation in NOTCH3 (OMIM #125310) and over 170 mutations have been identified to date[334,335]. Interestingly, the majority of the mutations involve loss or gain of cysteine residues in one of the 34 EGF repeats in the extracellular domain of NOTCH3[336]. The odd numbers of cysteines (5 or 7) per EGF repeat caused by CADASIL NOTCH3 mutations are thought to disrupt the formation of proper intra-molecular disulfide bonds. Although no logical explanation has been proposed, it is interesting to note that the majority of the mutations are clustered between EGFr-1–5 and the distribution of CADASIL associated missense mutations along the extracellular domain of NOTCH3 is uneven[335].
Whether CADASIL is caused by loss or gain of function of NOTCH3 has been under extensive debate [337]. Some CADASIL mutations behave as loss-of-function alleles of NOTCH3 based on ligand-receptor binding and signaling assays performed in cultured cells and in mouse models [338–342]. However, considering that heterozygous deletions of the NOTCH3 locus have not been associated with CADASIL in human patients, and that Notch3 knockout mice do not exhibit pathological phenotypes that are characteristic for the disease [343], the degree to which defects in Notch signaling contributes to the pathogenesis of this disorder remains unclear. Others propose that the pathogenesis of CADASIL is due to a toxic-gain-of-function (neomorphic effect) of NOTCH3 and that non-physiological intermolecular disulfide bonds formed between the free cysteine residues of NOTCH3 and other transmembrane and/or secreted proteins is the primary cause of disease [344–346]. The extracellular portion of NOTCH3 has been found to be associated with or included in the GOM[347–349], which also consists of numerous proteins including Clusterin and Collagen18α1/Endostatin[350]. However, it remains to be determined whether extracellular accumulation/aggregation of secreted and cell surface proteins in the GOM is due to direct interaction of these factors with mutant NOTCH3 protein. In addition, whether there is a causal connection between GOM formation and clinical symptoms found in CADASIL patients still needs to be investigated and clarified. Furthermore, since most studies have been performed only on a small subset of pathogenic mutations in NOTCH3, further studies on a spectrum of mutations are needed to reveal the full molecular pathology of the disease.
Mutations in NOTCH3 have also been found in patients with lateral meningocele syndrome (LMNS, OMIM #130720)[351] where de novo NOTCH3 variants are identified, and in a single family with an autosomal dominantly inherited infantile myofibromatosis 2 (IMF2, OMIM #615293)[352]. The former disease is characterized by distinct facial characteristics, hypotonia, hyperextensibility and meningocele-related neurologic phenotypes such as bladder dysfunction, while the latter disorder is characterized by formation of benign tumors in connective tissues that arise due to excessive mescenchymal cell proliferation. Other reported cases of infantile myofibromatosis have been linked to the PDGFRB (Platelet Derived Growth Factor Receptor Beta) gene (OMIM #228550), and the role Notch signaling in the pathogenesis of this disease is unknown. Both disorders have been proposed to be caused through gain-of-function mechanisms (late truncating mutations that delete the PEST domain for LMNS[351]; missense mutation in the NRR domain for IMF2[352]), but further functional studies and additional patient identification are necessary to reveal a clear genotype-phenotype relationship.
4.6. Other Mendelian diseases caused by mutations in Notch signaling pathway genes: γ-secretase complex related disorders as an example
In addition to the diseases described above, there are a number of Mendelian diseases that are caused by mutations in homologs of Drosophila genes that are known to be critical for Notch signaling. However, since many genes are pleiotropic and have functions outside of the Notch signaling pathway, it is not clear which aspect, if any, of the patient’s phenotypes can be explained by defects in Notch signaling.
For example, dominant missense mutations in PSEN1 (OMIM #607822, 600274, 172700) and PSEN2 (OMIM #606889), that encode catalytic subunits of the γ-secretase complex, cause rare early onset familial forms of Alzheimer’s disease (AD) and other forms of dementia. Although several studies have implicated the role of Notch signaling in AD pathogenesis [353], the primary mechanism by which mutations in PSENs cause AD seems to be through altered proteolytic processing of Amyloid Precursor Protein (APP), another well characterized substrate of the γ-secretase complex [354]. Additional dominant missense mutations in PSEN1 (OMIM #613694) and PSEN2 (OMIM #613697) have also been found in patients with dilated cardiomyopathy[355–357]. The functional consequences of these missense mutations are unclear and whether defects in Notch signaling may be contributing to this condition has not been investigated. Furthermore, loss-of-function mutations in PSEN1 and other components of the γ-secretase complex cause another type of disease known as familial acne inversa. This condition, also known as hidradenitis suppurativa, is a chronic relapsing skin inflammatory disease that has been linked to haploinsufficiency of PSEN1 (OMIM #613737), NCSTN (Nicastrin, OMIM #142690) and PSENEN (Presenilin enhancer gamma-secretase subunit, OMIM #613736). Since Notch signaling plays multiple key roles in the development and maintenance of the skin[358] and immune system[359], it has been proposed that defects in Notch signaling contributes to the pathogenesis [360], but additional experimental evidence is needed to strengthen this model.
Similarly, dominant mutations in POFUT1 (Protein O-fucosyltransferase 1, OMIM #615327)[361], POGLUT1 [Protein O-glucosyltransferase 1, OMIM #615696, this gene is also linked to muscular dystrophy (OMIM #617232))[362] and ADAM10 (OMIM #615537) [363] cause skin disorders that results in pigmentation defects (Dowling-Degos disease or reticulate acropigmentation of Kitamura). Considering that Notch regulates multiple aspects of melanocyte development[364], it is likely that defects in Notch signaling contribute to the pathogenesis of these diseases[365,366]. However, direct experimental evidence is necessary to test this hypothesis. Likewise, mutations in a number of genes encoding general cellular machineries that affect Notch receptor trafficking and activation (e.g. Clathrin-Dynamin mediated endocytosis, ESCRT, AP-3, HOPS, V-ATPase complexes) are also linked to diverse diseases but additional work is required to determine the degree by which Notch signaling defects contribute to the pathology of these disorders.
In summary, genes that have been well established to function in Notch signaling are linked to a number of Mendelian diseases. The fact that the Notch pathway is pleiotropic likeky contributes to the broad range of human phenotypes affecting a wide range of organ systems. In addition, the strict dosage dependence of the pathway may explain the involvement of both gain- and loss-of-function mechanisms and both recessive and dominant modes of inheritance leading to disease. Further investigations that focus on of the functional impacts of each pathogenic mutations will likely provide better mechanistic understandings of how specific phenotypes associated with these disorders may be explained by defects in Notch signaling.
5. Using Drosophila to study rare functional variants in genes linked to Notch signaling pathway and beyond
Advances in sequencing technologies are accelerating the pace of disease gene discovery [367]. Currently (February 2017), of 149 genes that have been linked to Notch signaling in Drosophila melanogaster, 130 are conserved in human (87%) and 48 (37%) have human homologs that are linked to Mendelian diseases based on FlyBase[368], a manually curated database for Drosophila genetics and biology, and OMIM[292]. Identification of some of these disease genes was made possible through whole-exome sequencing [315,306,304,305,363,362]. As more and more exomes and genomes are sequenced in research and clinical diagnostic laboratories using high-throughput sequencing technologies[369–371], new human diseases that are caused by mutations in genes that have been previously linked to Notch signaling in flies are likely to be identified. In addition, the list of novel rare variants of unknown significance (VUS) in known Notch-related disease genes will also likely to continue to expand. Proper interpretation of the functional consequences of these VUS will become critical for researchers to identify the underlying causes of disease and for clinicians to make medical decisions for patients in the era of personalized medicine.
For Notch-related disorders, a number of in vitro and in vivo assays in mammalian systems have been established to assess the function of disease-associated variants. For example, several Alagille syndrome linked mutations in JAG1 (p.L37S, p.P163L and p.R184H) were shown to affect subcellular localization, glycosylation, and signaling capability of JAG1 using skeletal muscle derived cell lines, leading to the proposal of a haploinsufficient (loss-of-function) model of disease pathogenesis[372,373]. In another study, however, two Alagille syndrome linked mutations in JAG1 (p.C284F and p.E1003X) were reported to exhibit a dominant-negative effect on Notch signaling when overexpressed in NIH3T3 cells[374].
Conflicting results obtained through in vitro experiments are typically resolved using in vivo model systems. To date, most in vivo studies that attempt to understand the functional consequences of disease-associated variants in Notch related diseases have been performed in the mouse (Mus musculus). One key advantage of mouse models is that one can screen for phenotypic similarities between the mutant mice and disease patients. For example, heterozygous inactivation of Rbpj in muce causes cardiac phenotypes that are often seen in human diseases[375]. Similarly, cardiac phenotypes seen in LVNC patients that carry mutations in MIB1 were successfully phenocopied in heart specific Mib1 knockout mice[314]. Importantly, reduced Notch1 signaling in the developing heart was observed in these animals suggesting that loss-of-function of MIB1 and subsequent reduction in Notch activation is likely to be associated with LVNC. Some studies in mice have used gene knock-in strategies to introduce analogous mutations into the mouse ortholog of the human gene to understand the function of specific disease-linked mutations. For example, one study modeled two CADASIL-linked mutations (p.C455R and p.R1031C) in mice and showed that these mutations behave as hypomorphic alleles[350]. Furthermore, Clusterin and Collagen18α1/Endostatin, materials found in GOM in CADASIL patient brain vessels, accumulated in brain blood vessels of the mice, proving a phenotypic link between the human patients and the mouse models. Although important insights into the role of disease associated NOTCH3 variants in vascular biology can be obtained by these types of studies, a potential confound of these mouse mutants is that they do not exhibit key features of CADASIL such as development of spontaneous stroke [350,376]. Similar arguments have been made for mouse knock-in models for AD-linked mutations in PSEN1 [377–382]. Nevertheless, these models provide valuable information about the role of the genes and variants in a physiological setting, a complex systemic environment that cannot be easily mimicked in cell or tissue culture based studies.
One large drawback for gene modification based experiments in mice is the cost and time that is required to generate reagents and to complete the analysis of a given variant. When hundreds of novel VUS are identified from large sequencing efforts, it is unrealistic and uneconomical to use the mice to study all of these variants in vivo. In vitro experiments can be used as a first line of screening prior to the generation of mouse models, but slight defects that may be amplified through intercellular feedback loops in vivo (e.g. during lateral inhibition and inductive signaling) may be missed through simple cell based assays. Furthermore, if the disease-linked variants affect animo acids that are not conserved between human and mouse, a knock-in strategy cannot be applied. Based on the deep biological knowledge of Notch signaling and rich genetic toolkits the community has generated to characterize this pathway[383–385], Drosophila can be a powerful tool to bridge this gap. Here, we will discuss several strategies to functionally characterize disease-associated variants using Drosophila, starting with the identification of the potential fly ortholog of a gene of interest. We will close this section by providing examples of such Drosophila studies that have been performed to study disease-associated genes involved in Notch signaling.
5.1. Using bioinformatics to aggregate existing knowledge and resources
The first step in disease-linked variant functional studies using Drosophila is to perform bioinformatics analyses to identify the strongest Drosophila ortholog candidate for the human gene of interest. There are a number of orthology prediction programs that use different algorithms and criteria to predict the most likely ortholog candidate [386]. User-friendly online tools such as DIOPT (Drosophila RNAi Screening Center Integrative Ortholog Prediction Tool)[387] and HCOP (Human Genome Organization Gene Nomenclature Committee Comparison of Orthology Predictions Search)[388] integrates a number of these programs to provide the users with an arbitrary score. The higher the DIOPT or HCOP scores are for a given gene combination, more likely the two genes are to be true orthologs. Due to the two rounds of whole genome duplication evens that likely to have occurred in ancestral vertebrates [389] (although there is still some debate [390]), there are many cases in which multiple human genes are orthologous to a single fly gene as seen for Notch (NOTCH1–4), Delta (DLL1,3,4) and Serrate (JAG1,2) (Table 1). Once a fly gene of interest is identified, one can determine whether the gene has been linked to Notch signaling in Drosophila by using PubMed[391] or FlyBase[368]. Information such as known gene function, expression patterns, physical interactors, available reagents and publication records can be obtained through these websites. A newly developed integrative online resource called MARRVEL (Model organism Aggregated Resources for Rare Variant ExpLoration) [392,393] integrates DIOPT [387], Flybase[368] as well as additional human genomics [292,394–398] and model organisms databases [399–404] to help the users to perform a wide survey of the gene and variant of interest. These searches are important to confirm that the gene/variant of interest is worth investigating in depth prior to initiating the any experiments in model organisms.
For genes that have been linked to Notch signaling in Drosophila, it is important to determine the context in which this link has been made and to find out the tools and experimental strategies that were used to make the conclusion. One gene may have been functionally studied using a clean null allele in the context of embryonic central nervous system development, while another gene may have been studied using tissue-specific RNAi expression in the developing wing margin without proper control experiments. By obtaining information about the biological context and experimental strategy that was used in previous studies, one can determine how to design a set of experiments to test the function of the variant of interest. It is also important to determine whether the reagents used in the previous studies are available through stock centers or individual laboratories. If the mutant or transgenic stocks are available from public stock centers such as BDSC (Bloomington Drosophila Stock Center) [383], DGGR (Drosophila Genomics and Genetic Resources)[405], VDRC (Vienna Drosophila Resource Center)[406] or from individual labs upon request, this will save time and resources. Additional genetic tools such as Notch signaling reporters[407] and classical alleles of core Notch signaling pathway genes that can be useful for signaling and genetic interaction studies are also available from some of these stock centers. Many monoclonal antibodies (e.g. anti-Notch, anti-Delta) and constructs/plasmids that are useful for Notch signaling studies in Drosophila [e.g. transgenic vectors, cDNA clones and BACs (Bacterial Artificial Chromosomes)] are also available from DSHB (Developmental Studies Hybridoma Bank) [385] and DGRC (Drosophila Genomics Resource Center) [384], respectively. In summary, by performing a thorough search of the existing knowledge and resources using online tools and databases, one can obtain sufficient information to design a set of experiments to test the functional significance of a variant of interest in Drosophila.
5.2. Selecting the best strategy to study the variant of interest in flies
One important consideration when studying a human missense variant in Drosophila is whether the mutated/altered amino acid is conserved or not. While there are some exceptional cases (see the TM2D3 case discussed below in Section 5.3.2), conserved amino acids tends to be functionally more important[408]. In addition, the conservation of the residue allows one to test the function of the variant in the context of the fly gene/protein. By introducing the analogous variant in a fly cDNA or genomic rescue construct and expressing them in the mutant background in Drosophila, one can test if the variant behaves differently from the wild-type/reference fly gene. Also, if the variant of interest is conserved, site-directed mutagenesis using CRISPR (Clustered Regularly Interspaced Short Palindromic Repeat)-Cas9 System can be employed to edit the endogenous fly gene to create a clean knock-in allele via homology directed repair (HDR)[409].
If the amino acid is not conserved, one needs to somehow “humanize” the fly gene to be able to test the impact of the variant. There are a number of strategies to achieve this, and one powerful strategy that our laboratory has been using recently is based on the T2AGAL4 system (Fig. 5A)[410]. This method allows one to generate a convenient “2-in-1” strain that can dramatically facilitate gene humanization experiments in Drosophila[411]. The first step is to introduce an artificial exon consisting of a splice acceptor (SA), ribosomal skipping T2A sequence, GAL4 [Yeast transcription factor that activates UAS (Upstream Activating Sequence)] coding sequence and a transcriptional termination (polyA) signal into a coding intron (introns flanked by two coding exons) of a gene of interest. Introduction of this cassette can be performed via CRISPR/HDR or through recombinase mediated cassette exchange (RMCE) of MiMIC (Minos-Mediated Integration Cassette) insertions[412,413]. MiMIC is an engineered versatile transposable element that has been extensively mobilized in the fly genome and can be used as an entry point to manipulate genes in many sophisticated ways [414–416]. By flanking the T2A-GAL4 cassette with inverted attP sites, one can further convert this line into a GFP-tagged protein trap line via RMCE to enable a number of sophisticated biochemical, cell biological and genetic experiments [411]. If the gene lacks an intron, the GAL4-polyA cassette can be knocked into the first coding exon via the CRISPR/HDR (Fig. 5B). The T2A-GAL4 and GAL4 knock-in strains function as loss-of-function alleles due to the polyA signal. At the same time, these cassettes produce a GAL4 protein that is expressed in the same temporal and spatial manner as the host gene. The T2A ribosomal skipping peptide ensures that the protein is physically separated from the host protein so that GAL4 can enter the nucleus [410,417]. Upon nuclear entry, GAL4 will drive the expression of a cDNA of interest under the control of UAS elements[77]. Hence, by combining the T2AGAL4/GAL4 knock-in lines with a UAS-human cDNA transgenic line, one can replace the fly protein with a human protein to determine whether the two are interchangeable. Easily scorable phenotypes such as lethality or sterility can be used as crude assays to determine whether the human protein can function in the fly body. If one observes a complete or partial rescue with a reference (wild-type) human cDNA, one can use this as a reference point to compare how well the variant cDNA functions [418,419]. Further rescue experiments of Notch related phenotypes (e.g. neurogenic, wing notching) or signaling defects (e.g. activation of Notch reporters or target genes) will provide information on whether the variant impacts Notch signaling in vivo.
Figure 5: Strategies to “humanize” Drosophila genes in vivo.
A) For genes that have coding introns (introns flanking two coding exons), one can insert a T2A-GAL4 cassette via CRISPR and HDR (homology directed repair). When the gene of interest is translated, the splice acceptor (SA) forces the splicing machinery to include the T2A-GAL4 cassette. The transcriptional termination site (polyA) stops the transcription, preventing the rest of the gene to be transcribed. When the transcript (mRNA) is translated, N-terminal of the fly protein is made but is prematurely truncated due to the T2A (2A) ribosomal skipping sequence, leading to generation of nonfunctional proteins in most cases. T2A sequence further allows the GAL4 protein to be translated, which in turn translocates to the nucleus to activate the expression of human cDNAs (wild-type/reference or mutant/variant) under the control of UAS elements. B) For genes that do not have a coding intron, one can knock-in a GAL4 in the fly gene of interest. GAL4 will be transcribed and translated in the same temporal and special manner as the fly gene, allowing one to express the human cDNA in a mutant background. Grey boxes: 5’ and 3’ untranslated regions. Orange box: Fly coding sequence (CDS).
In addition to this T2A-GAL4 strategy, one can also make use of mutant fly strains that have been previously characterized and try to rescue the mutant phenotypes using UAS-human cDNA transgenic lines and ubiquitous- or tissue-specific GAL4 drivers. To date, we have rescued a number of fly mutants by ubiquitous expression of human cDNAs [420–422,58,423–425], suggesting that many human genes have shared molecular functions and can replace the fly orthologs in vivo. A more rudimentary humanization experiment can be performed by co-expressing an RNAi against a fly gene together with a human cDNA. Furthermore, in addition to rescue/replacement based functional studies, one can perform over-expression based experiments in a wild-type background using the GAL4/UAS system to determine whether there are any differences observed when reference and variant forms are compared. This could be especially useful for cases in which a hypermorphic (gain-of-function), antimorphic (dominant negative), or neomorphic scenarios are suspected. However, ectopic over-expression based phenotypes observed through these studies need to be assessed with caution since they may not reflect the physiological function of the variant. Similarly, negative data may simply be due to the lack of sensitivity of the phenotype or assay that is being performed. Hence, positive data are strongly indicative that the variant has a functional impact in human, but one cannot rule out a candidate gene/variant due to negative data obtained from Drosophila studies.
5.3. Functional studies of disease associated variants in Notch signaling genes in Drosophila
Although functional studies of human disease associated variants in genes linked to Notch signaling have not been performed extensively in Drosophila, the following two examples related to Alzheimer’s disease illustrate the value of assessing Notch signaling related phenotypes in flies to elucidate the possible impact of disease-associated variants.
5.3.1. Early onset familial Alzheimer’s disease and PSEN1
Autosomal dominant mutations in PSEN1 are found in a number of families that exhibit rare early-onset forms of familial Alzheimer’s disease (FAD)[426]. There are >240 missense variants that have been identified to date [427] but potential impacts on PSEN1 function have not been experimentally defined for most of them. The age of onset of FAD varies from 24–65 years, suggesting that some alleles maybe more detrimental than others. By introducing 14 representative PSEN1 mutations found in conserved amino acids into the fly Psn homolog cDNA driven by an endogenous promoter, Seidner and colleagues performed a series of rescue experiments to determine whether there is any genotypephenotype correlation that they can identify that parallel the severity in human patients [428]. By assessing rescue of lethality, examining morphological defects in the wing margin, bristle and eye, and performing in vivo reporter assays in a Psn null mutant background, they were able to group the FAD-linked variants into three distinct classes, which correlated well with the severity of disease presentation in human patients. It is interesting to note that the authors also attempted rescue of the fly Psn null mutant with human PSEN1 or PSEN2 transgenes but they failed, suggesting that human PSEN1 and PSEN2 cannot function in the context of the fly γ-secretase complex. Humanization of the entire γ-secretase complex (Psn, nct, pen-2, aph-1) may circumvent the problem but this needs to be experimentally tested.
5.3.2. Late onset sporadic Alzheimer’s disease and TM2D3
Compared to FAD, the genetic causes of Late-onset Alzheimer’s disease (LOAD) remain to be defined. Since LOAD is much more common than FAD and found sporadically, a number of Genome-Wide Association Studies (GWAS), using common variants have been performed and a number of loci that increase the risk of LOAD have been identified [429,430]. Other than the well-established coding variants (p.C112R and p.R158C) in APOE (APOlipoprotein E, OMIM #104310)[431–433], however, the significance of most of these variants awaits to be experimentally verified. Through a recent exome-wide association study, the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium[434,435] identified a rare coding variant in a previously uncharacterized gene that has a strong effect size on LOAD[436]. A P155L variant in TM2D3 (TM2 domain containing 3) was associated with a ~7.5 fold chance of developing LOAD and a 10-year earlier age of onset in an Icelandic population. However, the study was not able to replicate this finding in other populations since this allele was 10 times less frequent in non-Icelanders. TM2D3 encodes a transmembrane protein whose function has never been studied in vertebrate species. Furthermore, the p.P155L variant was predicted to be benign using multiple mutation prediction programs, leading to skepticism that this variant has functional consequences. The fly TM2D3 homolog almondex (amx) was one of the earliest genes together with Notch, Delta, neur, mam, E(spl) and big brain (bib, endocing an Aquaporin-family protein), to be linked to Notch signaling based on its strong embryonic neurogenic phenotype when maternally mutated [4,5]. amx mutants undergo normal development, likely due to a large maternal contribution, but all embryos that are laid by homozygous or hemizygous (mutant over a deficiency of the locus) amx mutant females exhibit a strong neurogenic phenotype and die as embryos [437,5]. Although the molecular function of Amx is still unknown, genetic epistasis experiments have suggested that Amx likely functions at the S3 cleavage step of Notch activation [438]. Considering that PSEN1 and PSEN2, two genes that cause FAD also act at the same step in the Notch pathway, and that maternal-zygotic Psn null mutant embryos phenocopy the maternal amx mutant phenotype in Drosophila[38,39], the p.P155L in TM2D3 was an excellent candidate variant that may increase the risk of LOAD through regulation of the γ-secretase complex. Since the variant amino acid (p.P155) is not conserved between human and Drosophila, we humanized the fly amx gene by generating a genomic rescue construct in which the fly amx coding region has been replaced by the human sequence. Interestingly, the reference TM2D3 was able to partially rescue the neurogenic phenotype and lethality of the maternal amx mutant embryos, whereas TM2D3 with the p.P155L variant was not able to do so[436]. Hence, p.P155L associated with LOAD was shown to be a functional variant based on Notch-signaling related phenotypic assay performed in vivo, and further functional studies are ongoing to determine the precise molecular function of TM2D3/Amx in vivo.
In summary, genetic tools and phenotypic assays in Drosophila provide valuable information to assess the functional consequences of disease-linked variants in vivo. Even for conditions such as AD for which the pathogenic involvement of Notch signaling is still obscure, Notch signaling related phenotypes in Drosophila tissues such as the wing, bristle, and embryonic nervous system can be used as robust and reproducible phenotypic readouts to determine the functionality of disease-associated human variants of interest. Similar strategies can be employed to determine the functionalities of many VUS that are identified through massive sequencing efforts.
6. Conclusions
Notch signaling is a unique pathway that regulates diverse biological processes through a relatively simple and straightforward signal transduction mechanism. Studies in Drosophila have played a pioneering role in assembling the Notch signaling pathway, elucidating numerous factors that fine-tune it in diverse contexts. By combining a number of genetic tools and resources, fly researchers have uncovered a number of biological functions of this pathway in a variety of developmental and post-developmental settings.
Although Notch signaling in Drosophila has been extensively studied over the last century, exciting new discoveries continue to be made in the fly field that impacts the larger biomedical community. Large-scale screens using newer technologies will likely continue to expand the list of genes that regulate Notch signaling in vivo in Drosophila, which could subsequently be used as a starting point when studying the function of orthologous genes in vertebrates. Through efforts of clinicians and human geneticists, a number of human diseases that are caused by mutations in genes linked to Notch signaling have been discovered, increasing the significance of the pathway in human health. We foresee that such gene/disease lists will continue to expand through efforts in the human genomics field. Understanding the functional consequences of VUS is critical for these studies, and experiments in Drosophila can accelerate such efforts.
Moving forward, close communications and collaborations among Drosophila researchers, human geneticists and clinicians will provide a synergistic effect to quickly identify novel human disease linked genes, study the function of variants of interest, and begin to understand the biological function of these genes in vivo[439]. The rich knowledge regarding various biological contexts that are regulated by Notch signaling and the extensive genetic tools that are available to Drosophila researchers provide a unique advantage when studying novel human disease genes in the context of Notch signaling. Through further information exchange and collaborations with vertebrate biologists, biochemists, molecular biologists, structural biologists and bioinformaticians, such knowledge can further be translated to develop potential therapies for patients. Drosophila will continue to be at the forefront of the Notch signaling field, and discoveries made using the fly will provide valuable information to understand human pathology and possibly tame this pathway when necessary.
7. Acknowledgements
We apologize to our colleagues for not being able to cite their works. We thank Drs. Andrew K. Groves, Hamed Jafar-Nejad, Hillary K. Graves and Michael F. Wangler for constructive comments and helpful suggestions. S.Y. is supported by the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital (NRI Fellowship), the Naman Family Fund for Basic Research and the Caroline Wiess Law Fund for Research in Molecular Medicine (BCM Junior Faculty Seed Funding Program), Alzheimer’s Association (NIRH-15–364099), Simons Foundation Autism Research Initiative (Award#368479), and the National Institutes of Health (NIH, U54 NS093793). J.L.S. received support from the NIH (GMR2556929).
Abbreviations:
- AD
Alzheimer’s disease
- ADAM10
A Disintegrin and Metalloprotease 10
- AES
Amino-terminal Enhancer of Split
- ago
archipelago
- amx
almondex
- AOS
Adams-Oliver Syndrome
- AP-3
Adaptor Protein-3
- Aph
Anterior pharynx defective
- APOE
APOlipoprotein E
- APP
Amyloid Precursor Protein
- aPKC
atypical Protein Kinase C
- ARHGAP31
Rho GTPase-activating protein 31
- Arp2/3
Actin-related protein 2/3
- AS-C
Achaete-Scute Complex
- BAC
Bacterial Artificial Chromosome
- bib
big brain
- BDSC
Bloomington Drosophila Stock Center
- bHLH
basic Helix-Loop-Helix
- C. elegans
Caenorhabditis elegans
- CADASIL
Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts andLeukoencephalopathy
- CBP/CREBBP
CREB Binding Protein
- CDK8
Cyclin-Dependent Kinase 8
- CREB
cAMP response element binding protein
- cDNA
complementary DeoxyriboNucleic Acid
- CHARGE
Cohorts for Heart and Aging Research in Genomic Epidemiology
- CRISPR
Clustered Regularly Interspaced Short Palindromic Repeats
- CtBP
C-terminal Binding Protein
- DFS
Dominant Female Sterile
- DGGR
Drosophila Genomics and Genetic Resources
- DGRC
Drosophila Genomics Resource Center
- DIOPT
Drosophila RNAi Screening Center Integrative Ortholog Prediction Tool
- Dl
Delta
- DLL
DeLta-Like
- DOCK6
Dedicator Of Cytokinesis 6
- DSHB
Developmental Studies Hybridoma Bank
- dx
deltex
- E(spl)-C
Enhancer of split-Complex
- EGF
Epidermal Growth Factor
- EHBP-1
EH (Eps15 Homology) domain Binding Protein-1
- elav
embryonic lethal abnormal vision
- EMS
Ethyl MethaneSulfonate
- Eogt
EGF-domain O-GlcNAc transferase
- EP300
E1A binding protein P300
- ER
Endoplasmic Reticulum
- ESCRT
Endosomal Sorting Complexes Required for Transport
- FAD
Familial Alzheimer’s Disease
- FBXW7
F-BoX and WD repeat domain containing 7
- FHL1
Four and a H alf LIM domains 1
- FLP
FLiPpase
- Fng
Fringe
- FRT
Flippase Recognition Target
- GAP
GTPase-Activating Protein
- GEF
Guanine nucleotide Exchange Factor
- GFI1
Growth Factor Independent 1 transcriptional repressor
- glcNAc
N-Acetylglucosamine
- glp-1
Germ Line Proliferation defective-1
- GOM
granular osmophilic material
- Gro
Groucho
- GWAS
Genome-Wide Association Studies
- H
Hairless
- hAPF
hours After Puparium Formation
- HCOP
Human genome organization gene nomenclature committee Comparison of Orthology Predictions search
- HDR
Homology Directed Repair
- HES
Hairy and Enhancer of Split
- HEY
Hairy/Enhancer-of-split related with YRPW motif protein
- HOPS
HOmotypic fusion and Protein Sorting
- IMF
Infantile MyoFibromatosis
- JAG
JAGged
- kuz
kuzbanian
- l(2)gd1
lethal (2) giant discs 1
- LFNG
Lunatic FiNGe
- LIM
Lin11, Isl-1 and Mec-3
- lin-12
cell LINeage defective-12
- LMNS
Lateral MeNingocele Syndrome
- LNR
Lin-12/Notch Repeat
- LOAD
Late-Onset Alzheimer’s Disease
- LVNC
Left Ventricular NonCompaction
- mam
mastermind
- MAML
Mastermind-like
- MARRVEL
Model organism Aggregated Resources for Rare Variant ExpLoration
- MESP2
Mesoderm posterior bHLH transcription factor 2
- MFNG
Manic FriNGe
- mib
mindbomb
- MiMIC
Minos-Mediated Integration Cassette
- mRNA
messenger RiboNucleic Acid
- Nct/NCSTN
Nicastrin
- nej
nejire
- neur/NEURL
neutralized
- NEXT
Notch extracellular truncation
- NICD
Notch intracellular domain
- NRR
Negative Regulatory Region
- O-fut1
O-fucosyltransferase-1
- OMIM
Online Mendelian Inheritance in Man
- PDGFRB
Platelet Derived Growth Factor Receptor Beta
- pen/PSENEN
presenilin enhancer
- PEST
proline (P), glutamic acid (E), serine (S) and threonine (T)-rich
- POFUT1
Protein O-fucosyltransferase 1
- POGLUT1
Protein O-glucosyltransferase 1
- PTM
post-translational modification
- Psn/PSEN
Presenilin
- RBPJ
Recombination signal Binding Protein for immunoglobulin kappa J region
- RFNG
Radical FriNGe
- RIPPLY2
RIPPLY transcriptional repressor 2
- RMCE
Recombinase Mediated Cassette Exchange
- RNAi
RNA interference
- SA
Splice Acceptor
- SCDO
SpondyloCostal DysOstosis
- Sec15
Secretory 15
- Ser
Serrate
- SHARP
SMRT/HDAC1 Associated Repressor Protein
- shi
shibire
- SOP
Sensory Organ Precursor
- spdo
sanpodo
- SPEN
Split ENds family transcriptional repressor
- spl
split
- Su(dx)
Suppressor of deltex
- Su(H)
Suppressor of Hairless
- TBX6
T-box 6
- Temp
Tempura
- TLE
Transducin Like Enhancer protein
- TM2D3
TM2 domain containing 3
- UAS
Upstream Activation Sequence
- V-ATPase
Vacuolar-ATPase
- VDRC
Vienna Drosophila Resource Center
- VUS
Variant of Unknown Significance
- WASp
Wiskott-Aldrich Syndrome protein
- wg
wingless
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