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. Author manuscript; available in PMC: 2018 Dec 1.
Published in final edited form as: Mech Dev. 2017 Apr 23;148:11–17. doi: 10.1016/j.mod.2017.04.003

Regulating distal tip cell migration in space and time

Alyssa D Cecchetelli 1, Erin J Cram 1,2
PMCID: PMC5653462  NIHMSID: NIHMS873631  PMID: 28442366

Abstract

Gonad morphogenesis in the nematode C. elegans is guided by two leader cells, the distal tip cells (DTC). The DTCs migrate along a stereotyped path, executing two 90° turns before stopping at the midpoint of the animal. This migratory path determines the double-U shape of the adult gonad, therefore, the path taken by the DTCs can be inferred from the final shape of the organ. In this review, we focus on the mechanism by which the DTC executes the first 90° turn from the ventral to dorsal side of the animal, and how it finds its correct stopping place at the midpoint of the animal. We discuss the role of heterochronic genes in coordinating DTC migration with larval development, the role of feedback loops and miRNA regulation in phenotypic robustness, and the role of RNA binding proteins in the cessation of DTC migration.

1. General overview

Cell migration is essential for proper embryonic development, morphogenesis, immunity, wound healing and regeneration, and inappropriate cell migration can lead to devastating diseases such as metastatic cancer. Mechanisms that regulate cell migration are highly conserved (1, 2), therefore, studying cell migration in model organisms can yield key insights. The distal tip cells (DTCs) in the nematode C. elegans are an advantageous in vivo model for the study of cell migration. The two DTCs migrate away from each other along mirror-image paths, with the same timing in every individual, to produce two symmetrical gonad arms. Because C. elegans is translucent, this process can be visualized easily in living animals using cell-specific fluorescent markers or differential interference contrast microscopy (DIC) (Figure 1 A,B).

Figure 1. The Distal Tip Cell (DTC) in C. elegans takes a U-shaped migratory path during development.

Figure 1

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In the hermaphrodite, one DTC is found at the distal end of each gonad arm. A) DIC image with the DTC indicated by an arrow. B) Corresponding fluorescence image with the DTC (arrow), vulva (*), and embryos outlined by MIG-2∷GFP. C) Schematic representation of the anterior DTC's migration through all three phases of migration: phase 1 during L2 and early L3, phase 2 during L3, and phase 3 during L4. DTCs are designated by arrows indicating the direction of migration and the vulva by a diamond.

Towards the end of embryogenesis, the somatic gonad arises from two cells, Z1 and Z4 (3). These cells give rise to the somatic structures of the gonad including the DTCs, sheath cells, spermatheca and uterus. The two other cells of the primordial gonad, Z2 and Z3, give rise to the germ line (3). The gonad is surrounded by its own basement membrane (4), which is in contact with the basement membrane of the body wall muscles and the hypodermis (5). The basement membrane is secreted by the DTCs themselves and by nearby tissues. A thin layer of smooth muscle-like sheath cells also surrounds the gonad. Sheath cells migrate over the germ cells, and play an important role in proper gonad and germ cell development and maintenance (6–8).

The DTCs are leader cells that guide migration of the cells of the gonad through three migratory phases (9–11). Because of this, the resulting shape of the adult gonad arm reflects the migratory path taken by the DTCs. The DTCs are born during the first larval stage (L1) and reside at both sides of the primordium. The developing gonad elongates throughout larval development (3). During the second larval stage (L2) stage, the DTCs migrate along the ventral surface in opposite directions, towards the anterior and posterior ends of the animal (Phase I) (3). During the third larval stage (L3), the DTCs turn twice. First, the DTCs turn away from the ventral surface and migrate to the dorsal side of the animal where they turn once more towards the dorsal midbody (Phase 2). Finally, during the last larval stage (L4), DTCs migrate along the dorsal side of the animal towards the dorsal midbody (Phase 3). At the onset of adulthood, the DTCs cease migrating at the midline opposite the vulva (3, 12) (Figure 1, Figure 2A).

Figure 2. Defects in netrin signaling lead to a failure to execute phase 2 of DTC migration.

Figure 2

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A) In wild type animals, DTCs migrate dorsally at Phase 2, and back towards the midline during Phase 3,stopping adjacent to the vulva (*).Migration path marked with an arrow. B) In unc-5(e53) animals, DTCs fail to migrate dorsally during Phase 2, completing Phase 3 on the ventral side of the animal and stopping adjacent to the vulva (*).Migration path marked with arrows. Figure adapted from Levy-Strumpf et al. 2015 (21).

Regulators of DTC migration have been identified using both forward and reverse genetic screens (9, 11), and these include genes involved in the cytoskeleton, cell adhesion, and extracellular matrix (ECM), but also cell signaling, cell fate specification, gene expression, and developmental timing. Wong and Schwarzbauer, 2012 (13) provide a thorough overview of DTC migration, with emphasis on the sets of genes that regulate each phase of DTC migration. However, for the DTC to migrate, turn and stop correctly, migration must be regulated spatially and coordinated temporally with other developmental processes. Here, we focus on how the DTC “knows” where it is in time and space, specifically, on the most studied phases of migration, correct timing and placement of the first turn of the DTC (Phase 2), and DTC cessation at the onset of adulthood (end of Phase 3).

2. Spatial-Temporal coordination of the first turn of DTC migration

2.1 Netrin Signaling regulates the first turn of DTC migration

At the L3 stage of larval development, the DTCs reorient themselves, turning from the ventral basement membrane to the lateral hypodermal basement membrane. UNC-6/netrin signaling is the key regulator of this first turn (14). UNC-6/netrin is a laminin-like secreted protein that provides directional information to many types of migrating cells including neurons and the DTCs (15). UNC-6 and its receptors UNC-5 and UNC-40 are essential for this first turn and for migration of DTCs towards the dorsal muscle basement membrane (10, 16). UNC-5 receptors orient the movement of motile cells and neurons away from netrin cues (16–18). UNC-40 however, has both attractive and repulsive responsiveness to UNC-6 but functions to repel motile cells when in conjunction with UNC-5(16, 19). The UNC-5 and UNC-40 netrin receptors are both capable of responding to UNC-6 cues independently, but function best when working in combination (20). Mutations in unc-6, unc-5 or unc-40 cause Phase 2 DTC migration defects in which cells fail to make the turn to the dorsal side but instead continue to migrate on the ventral side of the animal (Figure 2B).

UNC-6 is considered to be distributed in a gradient along the ventral muscle basement membrane, peaking at the ventral midline (15, 22). unc-40 is expressed in DTCs of L2 thru L4 animals, however, unc-5 expression in the DTC is only observed at the time of DTC reorientation (19, 23). The activation of UNC-5 in the DTC during late L3 initiates DTC reorientation from the ventral to the dorsal side of the animal (23). Successful repulsion from the ventral side requires signals downstream of UNC-5. The exact mechanism by which netrin controls directional cell migration is not completely understood, however, netrin receptors can reorient cell direction by signaling through the Rho/Rac family GTPases, CED-10/Rac, and MIG-2/RhoG, that control remodeling of the actin cytoskeleton (24, 25). SRC-1, one of two C. elegans SRC non-receptor tyrosine kinases, can also bind and phosphorylate UNC-5 to initiate downstream signaling cascades (26, 27). In neurons, UNC-5 interacts with MAX-2, a p21 activated kinase (PAK) (28, 29), and in the DTC, MAX-2 regulates migration downstream of Rac (30). PAK-1, the other P21 activated kinase, also plays a role in DTC migration and cell shape through both a Rac dependent and a Rac independent GIT/PIX/PAK pathway (29, 30). Racs and PAKs normally function upstream of actin polymerization and/or microtubule disassembly, providing a possible link between netrin signaling and the actin cytoskeleton dynamics that drive reorientation and migration of the DTC.

2.2 Heterochronic genes regulate developmental transitions

Increased expression of UNC-5 clearly drives the ventral to dorsal turn, however, until recently, it was unclear what regulated the increased expression of UNC-5 during late L3. Although many studies suggested that heterochronic genes can regulate the expression of UNC-5 (31–36), a role for heterochronic genes in DTC migration had remained elusive.

In C. elegans, heterochronic genes regulate many stage-specific events, and play essential roles in ensuring that correct temporal developmental programs are executed at the appropriate developmental stage (37, 38). Loss or gain-of-function mutations in heterochronic genes cause precocious or retarded cell divisions or cell fate decisions. For example, the classic heterochronic genes lin-4/miR-125 and lin-14, a transcriptional regulator, are critical for the correct developmental timing of L1 hypodermal lineage fates. lin-4 expression at L1 negatively regulates translation of LIN-14, resulting in a drop in LIN-14 protein levels during L2, and thereby promoting the L2 hypodermal specific fate (37, 39). Loss of lin-14 results in precocious expression of the L2 lineage pattern. Over the past decade or so, roles for heterochronic pathways in DTC migration have begun to be identified. For example, the heterochronic gene DAF-12 is necessary for the up-regulation of unc-5 (23, 40). Below, we discuss DAF-12 and several other heterochronic genes that play critical roles in the ventral to dorsal turn in L3 and stopping of the DTC at the end of L4.

2.3 Heterochronic genes regulate Phase 2 of DTC migration

The timing of the DTC dorsal turn at L3 (Phase 2) is regulated by the combined function of several heterochronic genes; DAF-12, a steroid hormone receptor (31, 32); LIN-29, a zinc-finger transcription factor (33); DRE-1, a F-Box protein of a SCF ubiquitin ligase complex (34); and LIN-42, a homolog of the Period (Per) family of circadian rhythm proteins (Figure 3). All are necessary for proper execution of Phase 2 (35). Single mutations in daf-12, lin-29, and dre-1 have no effect on DTC turning, but double mutants prevent or delay DTC turning (34). This implies a role for hormone signaling, gene expression and protein degradation in DTC migration; however, how these proteins coordinate spatio-temporal regulation of DTC turning was poorly understood. A recent study by Huang, et al. identified a crucial regulator, the zinc-finger transcriptional repressor BLMP-1, a heterochronic gene that works with DAF-12, LIN-29 and DRE-1 to coordinate Phase 2 via unc-5 transcriptional regulation (36).

Figure 3. Phase 2 of migration is regulated by a network of heterochronicgenes.

Figure 3

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During phase 1 of migration, high BLMP-1 and LIN-42 keep LIN-29 levels low. Dafachronic acids (DA) are released, and bind to DAF-12 which promotes the L2 to L3 transition. DAF-12 up-regulation both represses BLMP-1 and activates UNC-5. In addition, DRE-1 is up-regulated at L3 further destabilizing BLMP-1 levels. A drop in BLMP-1 allows LIN-29 protein levels to increase and further repress BLMP-1. Low BLMP-1 levels and high LIN-29 and DAF-12 levels leads to an increase in UNC-5 and initiation of the ventral to dorsal turn of phase 2 of DTC migration. Green indicates high expression/protein levels, while red denotes a decrease in protein or expression levels. Strength of repression/activation is indicated by thickness of line/arrow. Diagram adapted from Huang, et al., 2014 (36).

BLMP-1 is expressed in the DTC prior to Phase 2. BLMP-1 prevents precocious turning by negatively regulating unc-5 expression in the DTCs (36). A genome-wide ChIPseq experiment showed that BLMP-1 binds upstream of unc-5, suggesting BLMP-1 might directly inhibit the transcription of unc-5 (41). Analysis of blmp-1p∷GFP reporter expression suggests that both LIN-29 and DAF-12 are necessary for blmp-1 down-regulation at L3 (36). DRE-1 depletion, on the other hand, had no effect on blmp-1 transcription but was necessary for BLMP-1 protein levels to drop later in L3. DRE-1 likely negatively regulates BLMP-1 stability through ubiquitin-mediated proteolysis (36). Down-regulation of BLMP-1 at L3 contributes to the upregulation of UNC-5 that initiates repulsion from the ventral surface via netrin signaling.

LIN-29 works in a redundant fashion with DAF-12 to activate unc-5 expression, and ubiquitous expression of LIN-29 results in precocious ventral to dorsal turning of DTCs (23, 36). BLMP-1 binds upstream and represses the expression of lin-29 (36, 42). The expression of lin-29 is also negatively regulated by LIN-42, although the mechanism of this repression is not known (35). Depletion of lin-42 results in precocious DTC dorsal turns and an up-regulation of lin-29, similar to blmp-1 mutants. However, the turn occurs substantially earlier in lin-42 mutants than in blmp-1 mutant animals (36). Therefore, it is likely that LIN-42 broadly regulates genes necessary for DTC repulsion from the ventral side, while BLMP-1 more specifically regulates the temporal expression of a few heterochronic genes, including lin-29.

In summary, Phase 2 of DTC migration is regulated by a tight set of feedback loops between heterochronic genes (Figure 3). At L2, high BLMP-1 and LIN-42 levels keep LIN-29 levels low. During late L2, dafachronic acids (DA) bind to DAF-12 promoting the L2 to L3 transition (40). DAF-12 is not sufficient to repress blmp-1, however DRE-1 up-regulation destabilizes BLMP-1 through ubiquitin-mediated proteolysis. Decreased BLMP-1 allows LIN-29 levels to rise and further repress blmp-1. What is important is that LIN-29 and DAF-12 both activate unc-5 expression, as well as repress BLMP-1. For UNC-5 levels to reach the threshold for turning, LIN-29 or DAF-12 must be active and BLMP-1 must be down-regulated (23, 36). This coordinated action allows UNC-5 to be expressed at the proper time to initiate ventral repulsion via netrin signaling (Figure 3).

3. Robustness in DTC migration

Why is this control system so complicated? A recent mathematical model suggests that these feedback loops may help stabilize the spatio-temporal regulation of UNC-5 expression (43). This multilayered system helps to explain why single mutations in these genes do not produce DTC migration defects (43). However, gene expression is inherently noisy (44–46). This feature helps to explain the variable penetrance and severity of DTC migration defects seen even in double mutant animals. For example, some blmp-1;daf-12 animals exhibit precocious DTC turns (31%), but often, DTC migration is normal (43%) (36, 43). In blmp-1;daf-12 animals, a decrease in LIN-42 levels results in early, but lower and more variable levels of unc-5 expression due to the absence of daf-12. The model suggests that the DTC will turn when and if the threshold level of UNC-5 is reached.

Another layer of robustness may be provided by microRNA (miRNA) regulation. miRNAs are small, non-coding RNAs that can regulate gene expression post-transcriptionally by repressing translation or destabilizing their mRNA targets. miRNAs are transcribed into pri-miRNA that is processed first by DRSH-1 into a 60-70 nucleotide (nt) molecule that can fold upon itself into a hairpin loop (47, 48). This pre-mRNA is exported from the nucleus, and processed by DCR-1/dicer into a 20-25 nt mature miRNAs (49, 50). miRNAs bind imperfectly to complementary sequences in the 3′UTR of target mRNAs to negatively regulate gene expression. Processing of miRNAs as well as small interfering RNAs (siRNA) involves incorporation into a RNA-inducing silencing complex (RISC), which includes members of the argonaute family (51).

Mutations in the argonaute alg-1, including null alleles and an antimorphic allele that seems to inappropriately sequester miRNAs, cause variable DTC migration defects (52). Several miRNAs which may be involved in gonad morphogenesis have been identified: mir-83, mir-1, mir-59, mir-34, mir-124, mir-247mir-797, and mir-259 (53). These genes are expressed in the DTC or in tissues that secrete the molecules that influence DTC migration. For example, mir-1 is expressed in the body wall muscles (54), mir-247mir-797 is expressed in the DTC (55), and mir-34 and mir-83 function in the DTC and/or muscles (56). Most of these factors have low penetrance defects when disrupted singly, but enhance DTC migration defects in combination (53), or when animals are exposed to stressful conditions (56). Although little is known about what genes miRNAs may target to regulate the robustness of DTC migration, several intriguing possibilities have been identified, including the small GTPase CDC-42 and the beta integrin PAT-3 (56). We searched mirWIP, a database of miRNA-mRNA target relationships (57), and identified alarge number of possible targets of these miRNAs relevant to DTC migration, including the netrin receptor UNC-6, and the transcriptional regulators LIN-29 and VAB-3 discussed in this article.

4. The DTC stops migrating at a specific place and time

A second example of spatio-temporal regulation of DTC migration occurs at the end of larval morphogenesis. In wild type animals, DTCs always stop migrating at the end of L4 when they reach the midpoint of the animal adjacent to the vulva (Figure 2A). This suggests the DTCs know both when and where to stop migrating, however, little is known about how the DTCs make these decisions.

Three well-characterized proteins that play a crucial role in DTC stopping are the alpha integrins INA-1 and PAT-2, and the transcription factor VAB-3/Pax6 (11, 58, 59). Integrins are transmembrane receptors that bind extracellular matrix and connect to the actin cytoskeleton (60). The beta integrin PAT-3, which forms an obligate heterodimer with either INA-1 or PAT-2, is expressed by the DTC throughout migration, and is required for all phases of DTC migration (9, 60, 61). In vab-3 mutant animals, the DTC migrates normally until the end of L4 and then, instead of stopping, continues to migrate, going around in circles near the vulva resulting in a “cinnamonroll” appearance of the end of the gonad arm (Figure 4A). VAB-3 regulates the expression of the integrins ina-1 and pat-2. For DTCs to stop appropriately, INA-1 is down-regulated and PAT-2 is up-regulated (58). Although the DTC does not stop migrating in vab-3 mutants, it does stay in the correct vicinity, near the vulva. This implies that while VAB-3 controls the timing of stopping, it is not necessary for the cell to determine the correct stopping location.

Figure 4. VAB-3 and CACN-1 are necessary for proper cessation of DTC migration.

Figure 4

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A) Loss of VAB-3 results in gonad arms that fail to stop migrating, continuing to migrate in circles near the vulva (*). B) CACN-1 depletion leads to gonad arms that migrate far past the vulva (*). An arrow marks the migration path of the DTC.

In the last few years, classical genetics and RNAi screens have been used to identify multiple additional regulators of DTC stopping. For example, CCDC-55, a coiled-coil containing protein of unknown function found in an operon with rnf-121 and rnf-5, two E3 ubiquitin ligases, CACN-1, another coiled-coiled containing protein, homologous to the IKB/cactus binding protein CACTIN, and MIG-39, a nuclear BED finger domain protein have all been found to be necessary for proper cessation of DTC migration (9, 63–65). Depletion of these genes via RNAi or by mutation results in gonad arms that migrate far past the vulva on the dorsal surface (Figure 4B).

Depletion of ccdc-55, rnf-121 and rnf-5 all independently cause low-penetrance DTC stopping defects, in which the DTC “overshoots” the correct stopping point (63). Because overexpression of RNF-121 causes gonad migration defects, including abnormal and extra turning, via excessive degradation of the beta integrin PAT-3 (66), it is possible that, like VAB-3, these genes regulate DTC migration through the proper spatio-temporal regulation of integrin expression. In addition, depletion of ccdc-55 enhances the overshoot phenotype in mutant rnf-121 and rnf-5 animals (63), suggesting that CCDC-55 works at least partially in parallel with RNF proteins to execute the stopping program. The molecular function of CCDC-55, and other relevant targets of RNF-121 and RNF-5 remain to be identified.

Depletion of cacn-1 by RNAi results in DTCs that continue to migrate during adulthood, rather than stopping at the end of L4. Often, the DTCs only stop migrating when unable to squeeze past the pharynx, or upon reaching the posterior end of the animal (65). Although the mechanism is not fully understood, CACN-1 and its homologs are emerging as regulators of splicing and/or post-transcriptional gene expression. For example, in Arabidopsis thaliana, CACTIN co-localizes with spliceosomal components(67), and human Cactin is associated with the C complex of the spliceosome (68–72). Similarly, C. elegans CACN-1 interacts with multiple splicing factors (73). Many of these proteins also result in significant overshoots when depleted by RNAi (73). Although CACN-1 may be necessary for the production of developmental stage-specific isoforms of cell migration genes, in C. elegans, proteins with homology to splicing factors commonly also function as RNA binding proteins to regulate gene expression post-transcriptionally (74). For example, the CACN-1 interacting protein and splicing factor PRP-17 is also a post-transcriptional regulator of key germ line developmental genes (75, 76).

MIG-39, a nuclear protein that most likely binds DNA, is also required for normal DTC stopping adjacent to the vulva (64). Although the overshoots caused by mutation of mig-39 are superficially similar to the cacn-1 and ccdc-55 phenotypes, closer analysis revealed that MIG-39 regulates the rate at which DTCs migrate during L4. Without mig-39, the DTC does not slow down, and therefore has bypassed the correct stopping point by the end of L4. Supporting the idea that CACN-1 and MIG-39 affect DTC migration independently, depletion of cacn-1 by RNAi enhanced the overshoot phenotype of the mig-39 mutants (64).

In summary, the phenotypes that result from disruption of VAB-3, CCDC-55, CACN-1 or MIG-39 suggest that the DTCs can interpret both spatial and developmental timing cues. MIG-39 may be needed to interpret spatial or temporal cues that let the DTC know the end of L4 (or the middle of the body) is approaching, and it is time to slow down. VAB-3 is needed for the temporal cue to stop migrating at the end of larval morphogenesis, whereas CCDC-55 and CACN-1 are needed to interpret both the spatial and timing cues that stop DTC migration.

Because stopping coincides with the developmental transition to adulthood, and because the decision to stop is under gene regulatory control, it seems likely that heterochronic genes will also play a role in the cessation of DTC migration. Although the authors do not comment on this feature, blmp-1 mutants seem to exhibit overshoots in addition to precocious turns (see Fig. 1 of reference (36)), possibly suggesting a possible active role for BLMP-1 in DTC stopping. An alternative hypothesis is that because blmp-1 DTCs turn early, they start their Phase 3 migration closer to the vulva.

Therefore, maintaining a normal pace would result in an overshoot. The resolution to this question will require further study of DTC phenotypes in animals in which heterochronic genes are disrupted later in larval morphogenesis after the execution of the Phase 2 turn.

5. Conclusions

Robust spatio-temporal regulation of cell migration is important not only for development, but also during the immune response and in wound healing. Many cell types can be activated to become migratory, follow cues to correct locations, and stop migrating at the desired location (77, 78). In addition, most cells in adult animals must remain stationary once they have reached their correct position, and reversion to a migratory phenotype can have adverse consequences such as the epithelial to mesenchymal transition (EMT), a hallmark of metastatic cancer (79, 80). In EMT, genes are often mis-expressed, leading to undesirable phenotypes. For example, inappropriate alternative splicing of ECM, cytoskeletal and migration genes can activate migratory behavior of human breast cancer cells (81). Similarly, defects in microRNA activity, and regulators such as the argonaute proteins have been correlated with Wilms Tumor, colorectal and gastric cancers (82–85). We hope that a deeper understanding of the spatio-temporal regulation of cell migration in the C. elegans system can help to identify genes, fundamental mechanisms and regulatory networks that can aid in the eventual development of therapeutics targeting cancer and other cell migration-related disorders.

Highlights.

  • Here, we review distal tip cell migration (DTC) migration in the nematode C. elegans.

  • We focus on the first turn taken by the DTC and on correct cessation of DTCmigration.

  • We discuss the role of heterochronic genes, miRNA regulation, and RNAbinding proteins in DTC migration.

Acknowledgments

This work was supported by a grant from the National Institutes of Health NIGMS (GM085077) to E.J.C.

Footnotes

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