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. 2013 Dec 5;8(1):26–32. doi: 10.4161/fly.27424

Roles of Hox genes in the patterning of the central nervous system of Drosophila

Alicia Estacio-Gómez 1, Fernando J Díaz-Benjumea 1,*
PMCID: PMC3974890  PMID: 24406332

Abstract

One of the key aspects of functional nervous systems is the restriction of particular neural subtypes to specific regions, which permits the establishment of differential segment-specific neuromuscular networks. Although Hox genes play a major role in shaping the anterior-posterior body axis during animal development, our understanding of how they act in individual cells to determine particular traits at precise developmental stages is rudimentary. We have used the abdominal leucokinergic neurons (ABLKs) to address this issue. These neurons are generated during both embryonic and postembryonic neurogenesis by the same progenitor neuroblast, and are designated embryonic and postembryonic ABLKs, respectively. We report that the genes of the Bithorax-Complex, Ultrabithorax (Ubx) and abdominal-A (abd-A) are redundantly required to specify the embryonic ABLKs. Moreover, the segment-specific pattern of the postembryonic ABLKs, which are restricted to the most anterior abdominal segments, is controlled by the absence of Abdominal-B (Abd-B), which we found was able to repress the expression of the neuropeptide leucokinin. We discuss this and other examples of how Hox genes generate diversity within the central nervous system of Drosophila.

Keyword: development, Hox genes, central nervous system, Drosophila, cell fate specification

Neurogenesis in Drosophila

The Drosophila central nervous system (CNS) can be divided into the brain and the ventral nerve cord (VNC), the equivalents of the vertebrate brain and spinal cord, respectively. The VNC develops from a sheet of neuroectodermal cells located in the ventrolateral region of the embryo. During embryonic neurogenesis, patterning genes act in the anteroposterior and dorsoventral axis of the embryo to create a cartesian grid of positional information from which Drosophila neural progenitors, the neuroblasts, delaminate. In the VNC, which contains 3 subesophagic, 3 thoracic and 10 abdominal segments, each neural hemiunit or hemineuromere contains an initially invariant array of 30 neuroblasts (NBs), although gnathal and most posterior abdominal segments (A8–9) contain a lower number. Neuroblasts are named according to their position in rows (X) and columns (Y; NBX-Y. Fig. 1A) and can be identified by their position, time of delamination, and the unique combination of molecular markers they express (reviewed in 1).

graphic file with name fly-8-26-g1.jpg

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Figure 1. (A) Pattern of neuroblasts (circles) in a standard right hemineuromere of the stage 11 embryo. Each of these units contains 30 neuroblasts, which are named with reference to a Cartesian grid divided into 6 columns and 7 rows. Neuroblasts that delaminate from the posterior compartment are indicated (gray). The vertical line on the left indicates the midline. Anterior is up. (Adapted from 46) (B) Pattern of expression of Hox genes in the anteroposterior axis of the Drosophila ventral nerve cord. Equivalences between parasegments and segments are indicated. SE: subsesophagus, Th: thorax ad Ab: abdomen. (Adapted from 9) (C) Diagram summarizing the different actions of the Hox genes of the Bx-C in the production of ABLKs. The colored horizontal lines represent the periods of activity of the corresponding gene products.

In principle, neuroblasts located in equivalent positions in different segments acquire the same fate and are called serial homologs.2,3 However, 7 of the 30 serially homologous embryonic lineages have been shown to include different subsets of cells in the thoracic and abdominal segments, and it is now accepted that the expression of Hox genes is behind these regional divergences.4–7 In addition to this spatial control, there also exists temporal regulation whereby distinct temporal windows are defined. This involves the sequential expression in neuroblasts of the so-called temporal transcription factors: Hunchback (Hb), Krüppel (Kr), Pdm, Castor (Cas), and Grainyhead (Grh). As result, the progeny produced in a given time window acquire a specific identity that contributes to the generation of cell diversity (reviewed in 8).

This first embryonic period of neurogenesis generates the larval nervous system, at the end of which some embryonic neuroblasts (eNBs), mostly abdominal, die by apoptosis.9 The remaining embryonic progenitors, about 23 per thoracic hemisegment and 3–6 in abdominal regions, enter quiescence, a non-proliferative state that extends to the end of the first larval stage.10 After this, postembryonic neuroblasts (pNBs) resume mitotic activity and generate, in a second round of neurogenesis, the progeny that will form the adult CNS (reviewed in 11).

In addition to their early role in shaping large cellular territories, Hox genes influence the activities of individual cells, controlling processes in the CNS such as programmed cell death,12–15 proliferation,9,16,17 and cell specification.13,15,17–21 (Table 1)

Table 1. Actions of Hox genes within the central nervous system of Drosophila.

Gene Level of action described Role in the CNS Reference
Ubx and abd-A neuroectoderm Distinction between NB1–1T and A progeny. 18
Abd-B and caudal neuroectoderm Repression of formation of several NBs in PS15; e.g.NB7–3. 15
Antp neuroblasts Entry into quiescence of NB3–3T 16
Bx-C, hth and exd neuroblasts Induction of cell cycle exit of NB5–6A at stage 12. 17
abd-A neuroblasts Prevention of entry into quiescence of NB5–5A. 21
abd-A neuroblasts Induction of apoptosis in abdominal postembryonic neuroblasts 12
abd-A neuroblasts Continued proliferation of NB3–3A 16
abd-A and Abd-B neuroblasts Downregulation of CycE in NB6–4A. 19,31,32
Antp, hth and exd neuroblasts and neurons Activation of Ap cluster determinants: collier, dac. 17
hth neuroblasts and neurons Subdivision of the Cas temporal window of NB5–6T at stage 13. 17
Antp neurons Survival of the GW motoneuron of NB7–3 and anterior motoneuron of NB2–4T 13
Antp neurons Downregulation of dimm/dac in the equivalent Va neurons in thorax. 20
Ubx neurons Apoptosis of the GW motoneuron of NB7–3 and the anterior motoneuron of NB2–4T 13
Ubx neurons Expression of dimm in Va neurons. 20
Ubx and abd-A neurons Specification of the ABLKs of NB5–5A. 21
Ubx and abd-A neurons Maintenance of expression of Lk in ABLKs. 21
abd-A neurons Expression of Capa in Va neurons. 20
Abd-B neurons Prevention of apoptosis of dMP2 and MP1 pioneer neurons 14
Abd-B neurons Programmed cell death in the Va neurons of A5–8 segments. 20
Abd-B neurons Repression of Lk expression in segment A8 in the embryo and in segments A5–8 in larvae. 21
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About Hox Genes

Hox genes were first discovered in Drosophila but they are present in most animal phyla studied. In the fly, molecular cloning showed that they were expressed in particular subdomains along the head-to-tail axis of the organism, providing cellular and tissue identities. Typically, mutation of a given Hox gene results in the transformation of part or all of an affected segment into the likeness of another segment, a phenomenon called homeotic transformation. For instance, gain-of-function alleles of Antennapedia (Antp), a Hox gene that is necessary for the development of the adult leg, leads to transformation of the antennae into legs.22

Hox genes encode homeodomain transcription factors and are typically organized in gene complexes. There are 2 of these complexes in Drosophila: the Antennapedia-complex (Antp-C), which specifies segments in the head and anterior thorax, and the Bithorax-Complex (Bx-C), which specifies segments of the posterior thorax and the abdomen (Fig. 1B). Similarly, there are at least 4 Hox complexes in vertebrates, probably the result of duplications of an ancestral cluster.23 Also, in order to increase their target specificity, Hox proteins sometimes make use of cofactors that cooperate with them in DNA binding and in selecting DNA binding sites. The best-characterized cofactors are all TALE (3 amino acid loop extension) homeodomain proteins. In Drosophila these are Extradenticle (Exd) and Homothorax (Hth) (reviewed in 24, 25).

Hox genes are mainly regulated at three levels: transcriptional regulation by earlier segmentation genes, by the Polycomb/trithorax group of proteins, and by Hox proteins themselves; in the latter case the products of more posterior Hox genes repress more anterior genes, a process called “posterior prevalence.” Additionally, it has been shown that target functions of Hox genes are highly context-dependent (reviewed in 25,26).

We will now review recent examples in which the expression of Hox genes provides segmental diversity within the Drosophila CNS.

How do Hox genes provide diversity in the CNS?

In Drosophila, Hox genes are expressed in the neuroectoderm of the corresponding segments, but after NB delamination their expression fades away to be later reactivated in individual cells, NBs or postmitotic neurons, as part of their genetic combinatorial code.17 This contrasts with their expression in the ectoderm in early embryonic stages, where once their ON or OFF state is established it is maintained throughout the rest of development (reviewed in 27); however, it is similar to the behavior observed in the vertebrate CNS, where certain Hox genes are expressed in a narrow time window during early development (reviewed in 28).

Hox genes can perform their roles in cell specification at the level of the neuroectoderm, neuroblast and/or postmitotic progeny (reviewed in 29). At the neuroectodermal level, the expression of Ubx and abd-A in the neuroectoderm of the corresponding abdominal region is necessary and sufficient for NB1–1 to generate different lineages in the thoracic and abdominal segments.18 Thus, NB1–1T produces 2 motoneurons and 10 interneurons, whereas its abdominal counterpart gives rise to 1 motoneuron, 6 interneurons and 3 glial cells.

In addition, segmental diversity can be produced by the presence of different initial numbers of progenitors in the different segments of the VNC. For example, Birkholz et al.15 have shown that Abd-B inhibits the formation of a specific set of NBs in the most posterior abdominal segments. Specifically, they found that there were more neuroblasts in parasegment 15 (i.e., the posterior half of abdominal segment 9 and anterior half of abdominal segment 10) in Abd-B mutant embryos than in the wild-type, one of these extra progenitors being NB7–3 and its lineage. These authors checked that this phenotype was not due to a pro-apoptotic role of Abd-B, as has been reported elsewhere,26 since apoptosis-deficient mutant embryos did not contain ectopic NB7–3 clusters, although they found that Abd-B induced programmed cell death in a subset of cells of the NB3–3 lineage. Conversely, strong expression of Abd-B in the neuroectoderm repressed the formation of NB7–3 in more anterior parasegments. When Abd-B was overexpressed together with the baculovirus apoptosis inhibitor p35, the clusters of NB7–3 were not rescued; this indicates that their disappearance, upon Abd-B misexpression, was not due to death but to a homeotic transformation to more posterior parasegments where NB7–3 clusters were not produced. Interestingly, they found that Abd-B needed the cooperation of the product of the paraHox gene caudal to perform its function.

Since lethal of scute was found to be a putative Abd-B targets,30 Birkholz et al.15 speculated that it prevented the formation of these neuroblasts in the more posterior segments of the VNC by repressing the formation of neural equivalence groups. However, overexpression of Abd-B in more anterior segments was unable to produce complete transformations toward the number of NBs present in PS15. Therefore, other mechanisms may be responsible for suppressing the formation of neuroblasts in the more posterior regions.

At the level of the neuroblast it has been shown for the NB6–4 lineage that Hox gene products specify the formation of different progeny in the thoracic and abdominal segments. NB6–4T induces the formation of both neurons and glial cells from their respective neural and glial precursor, whereas its abdominal counterpart generates only glial cells. This is due to a first asymmetric division in the thoracic NB6–4, in which the homeodomain gene Prospero (Pros), which activates the expression of the genes glial cell missing and reversed polarity, is only inherited by the glial precursor; this is followed by a symmetric division in the NB6–4 in the abdomen, where both daughter cells receive Pros and subsequently activate glial identity. Technau et al. have shown that the cell-cycle regulator gene CyclinE (CycE) and the Hox genes abd-A and Abd-B establish these differences.19,31,32 CycE is able to confer neuronal fate due to its ability to inhibit Pros by promoting cortical localization,33 which maintains stem cell behavior. CycE expression in NB6–4A is downregulated by Abd-A and Abd-B in abdominal segments; therefore, the absence of CycE allows the action of Pros in the nucleus, so activating glial fates. This function of CycE is independent of its role in cell-cycle regulation and is cell autonomous, as it is able to produce cell-fate transformations in other serially homologous neuroblast lineages (NB1–1 and NB5–4) when mutated or overexpressed.

At the postmitotic level, elements of the Hox complexes also contribute to the segment-specific appearance of the Va neurons, which express the neuropeptide Capa.20 They are only present in abdominal segments A2–4, and from stage 17 onwards; they are located on the ventral surface of the VNC, and are therefore called ventral-abdominal (Va) neurons. These neurons can be labeled, before the activation of Capa, by the co-expression of the neuropeptidergic master gene dimmed (dimm) and its cofactor dachshund (dac). At stage 15, Dimm/Dac positive cells are present in almost all abdominal segments. However, only the Va neurons in A2–4 differentiate as Capa-expressing neurons. Abd-A is required to specify Va neurons as Capa neurons, and therefore its lack of expression in A1 explains why Capa-expressing neurons are not generated in this segment. Likewise, Ubx is necessary in the single pair of A1 Dimm/Dac Va neurons for them to express dimm, but it is not known if they differentiate into neuropeptidergic neurons, and if so, which neuropeptide they express. On the other hand, Abd-B induces programmed cell death of the Va neurons in segments A5–8. Lastly, Antp downregulates dimm and dac in thoracic segments.

Integration of Hox Genes with Temporal Information

Although Hox gene function originally acts in giving identity to different segments and so generating diversity along the main axis of the embryo, further studies have revealed that some Hox genes act in the specification of single cell types. That is the case for labial during the generation of copper cells in the gut, and for abd-A in specifying oenocytes;34,35 in the former case it acts cell autonomously, whereas in the latter it specifies the fates of neighboring cells.

In the CNS, NB5–6 provides an example not only of how Hox genes act at the level of individual neuroblasts and neurons, but also of how this positional information is integrated with temporal cues to generate specific cell types, e.g., the cluster of apterous (ap)-expressing neurons restricted to the 3 thoracic segments.17

The Ap-cluster neurons are the last cells produced by the thoracic NB5–6. They consist of 4 distinct (Ap1–4) neurons defined by the expression of the transcription factors Ap and the cofactor Eyes absent (Eya). Moreover, Ap1 and Ap4 are neuropeptidergic and can also be identified by Nplp1 and FMRFamide expression, respectively. Baumgardt et al. found that these neurons were specified in a Cas/Grh temporal window, and that Cas triggered the activation of collier, squeeze, and grh, each of which is needed to specify the correct fates of the 4 Ap-cluster neurons.36 Subsequently it turned out that the absence of Ap neurons in the abdominal regions was due to the combined action of the Bx-C gene products and their cofactors Hth and Exd, which direct NB5–6A to exit the cell cycle at stage 12, before the neuroblast passes through a Cas temporal window, so avoiding the formation of Ap neurons in abdominal segments. Antp, together with Hth and Exd, acts in thoracic segments to activate Ap cluster determinants. Moreover, these authors showed that an increase of hth expression at stage 13 plays an instructive role, subdividing the large Cas temporal window into 2 sub-windows, an early Cas and a later one that specifies the Ap-cluster window. Since this increase in hth expression was global, they speculated that Hth might act similarly in other lineages. Lastly, they found that Ap cluster equivalents were also present in more anterior segments, i.e., subesophageal and brain segments, but that the lack of Antp prevented their specification.

Actions of Hox Genes in Controlling Segment Diversity Throughout Development

To shed light on the mechanisms employed by Hox genes in patterning the CNS spatially and temporally, we have studied how they sculpt the segment-specific appearance of the abdominal leucokinergic neurons (ABLKs), which appear in both larval and adult stages and that are characterized by the expression of the neuropeptide, leucokinin (Lk) (Fig. 1C).21

ABLKs are generated during embryonic neurogenesis by NB5–5 in the first to the seventh abdominal segments of the VNC, producing a fixed number of 7 ABLKs per hemiganglion (embryonic ABLKs: eABLKs).37 We observed that the number of ABLKs increased during pupal stages, reaching an average of 11 in 4-day-old adults. We wondered when these new cells were generated; to find out we performed lineage-tracing experiments labeling the progeny of all pNBs. It turned out that of the Lk-expressing neurons seen in adult ganglia only around 4 cells were labeled. Therefore, the other ABLKs that we identified in adults were generated by the end of the 2nd instar larval stage during postembryonic neurogenesis (postembryonic ABLK: pABLKs), and started to express Lk in pupal stages.

We subsequently wished to know if both eABLKs and pABLKs were generated by the same neuroblast. In abdominal segments there are only 3 neuroblasts remaining, and these are identified according to their position in the VNC: ventrolateral (vl), ventromedial (vm) and dorsolateral (dl) postembryonic neuroblasts; however, how their identities related to the embryonic ones was not known. First, by co-expression of different markers we discovered that pABLKs came from the vl pNB. Thereafter we concluded that the embryonic NB5–5 and the vl pNB were the very same neuroblast. Thus, this neuroblast gives rise to eABLKs and then enters quiescence and resumes mitotic activity, producing the pABLKs that we detected from the pupal stages onwards. Having obtained these results we set out to explore the functions of the Hox genes in regulating this pattern of Lk-expressing cells. We observed that none of the Hox genes except Ubx and abd-A were redundantly required to specify eABLKs, and to maintain them in the adult stage. Accordingly, eABLKs expressed both Ubx and Abd-A in segments A2–7 and only Ubx in A1.

Surprisingly, overexpression of abd-A produced ectopic ABLKs in first instar larvae, and from other experiments we concluded that this phenotype was probably due to the ability of Abd-A to prevent entry of NB5–5 into quiescence and therefore to promote the generation of postembryonic progeny during embryonic neurogenesis. In the same mutant background we observed that these additional ABLKs were mostly restricted to the anterior-most abdominal segments, suggesting a role of Abd-B in repressing the appearance of pABLKs. Indeed, when Abd-B was removed, 1 extra ABLK arose in each A8 hemisegment of first instar larvae. In the same way, in the adult, up to 15 ABLKs per hemiganglion could be seen upon loss of Abd-B. Conversely, ectopic expression of Abd-B eliminated all eABLKs, and this phenotype was not rescued when apoptosis was inhibited. These observations suggested that Abd-B was able to repress either the ABLK fate or the expression of Lk. Consistent with this, Abd-B-RNAi overexpression from first instar larvae produced an extra ABLK in A8 in third instar larvae, indicating that the role of Abd-B is to suppress the expression of the neuropeptide Lk but not ABLK-neuronal fate; thus, as soon as Abd-B is removed from a neuron, Lk expression is de-repressed.

We also found that misexpression of hth produced extra ABLKs in the thoracic segments, where Antp is the only Hox gene expressed, suggesting that it is able to induce ABLK fate if enough Hth is provided. We obtained a similar result overexpressing the Hox gene Sex combs reduced (Scr); this produced ectopic ABLKs in both thoracic and A8 segments, which was surprising since Scr is expressed in PS2, where Lk is not normally expressed.

Role of Abd-B as a Sensor of the Enviromental Conditions of the Larva

In addition to the 3 main mechanisms controlling the expression of Hox genes in embryonic development referred to above, a wealth of experimental data indicates that modulation of chromatin state, long non-coding RNAs, alternative RNA processing and miRNA also modulate their expression.25 Multiple functional links between all these mechanisms have also been reported. This functional coupling between molecular mechanisms controlling gene expression seems to be a general phenomenon.38 From this interconnected network of Hox regulatory interactions has emerged the idea that robustness in the expression of Hox genes is necessary to avoid the disruptive effects of intrinsic and extrinsic fluctuations in embryonic environment and so ensure successful outcomes.25

However, in postembryonic development, when Hox genes seem to be involved in very different processes that account for terminal differentiation functions more than global patterning, this robustness could be counterproductive. Thus, while in embryonic neurogenesis the number of neurons of different types is very strictly specified, in postembryonic neurogenesis specification seems to be more plastic. This can be seen not only in the number of neurons generated, but also in the types produced, as described for the mushroom bodies lineages, in which nutritional conditions can modify the numbers of specific cell types within the lineage.39 Similar variability can be observed in the number of postembryonic neurons that produce neuropeptides, for instance, in the number of neurons producing the neuropeptide leucokinin or bursicon in the adult fly.21,40 Thus, the number of Lk-expressing neurons in the adult CNS varies depending on the environmental conditions and on the number of copies of Abd-B. This has led us to suggest that the level of expression of Abd-B might be affected by the environmental conditions of the larva and so control the number of neurons that produce leukoquinin.21

Phenotypic plasticity (polyphenism) as a result of changes in the environmental conditions is widely reported in insects.41 Environmental effects on the expression of patterning genes are also suggested by the variation in the number of segments found in populations of some species of centipedes.42,43 Although so far, to our knowledge, Hox genes have not been ascribed, in any of the reported cases, to be behind the mechanisms by which environmental changes are sensed, integrated and transformed into a response.

Concluding Remarks

Hox genes contribute to cellular diversity at different levels and at different times in development. In the earlier stages of embryogenesis, they act on a large ensemble of cells to establish the major body plan along the anteroposterior axis. Here, their actions are instructive, meaning that they impose the same developmental fate on all cells in which they are expressed, independent of the specific cellular context of each cell. Later on, as the examples within the CNS referred to above reveal, Hox genes also act in a more permissive manner in that the effects of their actions vary and depend on the cellular context of each cell and the precise time in development. For instance, in a single region Abd-B can inhibit the formation of NB7–3 without causing cell death, whereas it induces apoptosis in a subset of cells of the NB3–3 lineage.15 This points to the existence of a large number of targets of Hox genes; in fact Hox homeodomains recognize “AT”-rich DNA sequences of the form, TAAT [t/g] [a/g], corresponding to the so-called Antp group of homeodomains.44,45 There are around 86 000 copies of these sequences in the Drosophila genome, more than 5 times the number of annotated protein-coding genes. Although these sequences can be also bound by many non-Hox homeodomains, the fact that Hox proteins are able to recognize so many sites warns us, first, that regulation of Hox-targeted genes does not rely on homeodomain DNA recognition properties alone, but also depends on cofactors and specific cellular contexts; and second, that Hox genes are widely employed during development and most likely establish tightly controlled and complex genetic hierarchies.

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Acknowledgments

We are grateful to members of the lab for comments on the manuscript.

Funding

This work was supported by a pre-doctoral fellowship from the Ministerio de Educación to A.E.G. [AP2008–00397], grants from the Ministerio de Ciencia e Innovación [CSD2007–00008 and BFU2011–24315] to F.J.D.B., and an institutional grant from the Fundación Ramón Areces to the Centro de Biología Molecular-Severo Ochoa (CBM-SO).

Estacio-Gómez A, Moris-Sanz M, Schäfer AK, Perea D, Herrero P, Díaz-Benjumea FJ. Bithorax-complex genes sculpt the pattern of leucokinergic neurons in the Drosophila central nervous system. Development. 2013;140:2139–48. doi: 10.1242/dev.090423.

Footnotes

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