mig-5/Dsh controls cell fate determination and cell migration in C. elegans

Department of Biology, Johns Hopkins University, Baltimore, Maryland, United States
Developmental Biology (Impact Factor: 3.55). 11/2006; 298(2):485-97. DOI: 10.1016/j.ydbio.2006.06.053
Source: PubMed


Cell fate determination and cell migration are two essential events in the development of an organism. We identify mig-5, a Dishevelled family member, as a gene that regulates several cell fate decisions and cell migrations that are important during C. elegans embryonic and larval development. In offspring from mig-5 mutants, cell migrations are defective during hypodermal morphogenesis, QL neuroblast migration, and the gonad arm migration led by the distal tip cells (DTCs). In addition to abnormal migration, DTC fate is affected, resulting in either an absent or an extra DTC. The cell fates of the anchor cell in hermaphrodites and the linker cells in the male gonad are also defective, often resulting in the cells adopting the fates of their sister lineage. Moreover, 2 degrees vulval precursor cells occasionally adopt the 3 degrees vulval cell fate, resulting in a deformed vulva, and the P12 hypodermal precursor often differentiates into a second P11 cell. These defects demonstrate that MIG-5 is essential in determining proper cell fate and cell migration throughout C. elegans development.

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    • "similar to that published for mig-5 alleles (Walston et al., 2006). Simultaneous removal of the function of both dsh-2 and mig-5 by RNAi results in lethality during mid-gastrulation (Walston et al., 2004; our unpublished observations), precluding analysis of later requirements . "
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    ABSTRACT: Dishevelleds are modular proteins that lie at the crossroads of divergent Wnt signaling pathways. The DIX domain of dishevelleds modulates a beta-catenin destruction complex, and thereby mediates cell fate decisions through differential activation of Tcf transcription factors. The DEP domain of dishevelleds mediates planar polarity of cells within a sheet through regulation of actin modulators. In Caenorhabditis elegans asymmetric cell fate decisions are regulated by asymmetric localization of signaling components in a pathway termed the Wnt/beta-catenin asymmetry pathway. Which domain(s) of Disheveled regulate this pathway is unknown. We show that C. elegans embryos from dsh-2(or302) mutant mothers fail to successfully undergo morphogenesis, but transgenes containing either the DIX or the DEP domain of DSH-2 are sufficient to rescue the mutant phenotype. Embryos lacking zygotic function of SYS-1/beta-catenin, WRM-1/beta-catenin, or POP-1/Tcf show defects similar to dsh-2 mutants, including a loss of asymmetry in some cell fate decisions. Removal of two dishevelleds (dsh-2 and mig-5) leads to a global loss of POP-1 asymmetry, which can be rescued by addition of transgenes containing either the DIX or DEP domain of DSH-2. These results indicate that either the DIX or DEP domain of DSH-2 is capable of activating the Wnt/beta-catenin asymmetry pathway and regulating anterior-posterior fate decisions required for proper morphogenesis.
    Full-text · Article · May 2009 · Developmental Biology
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    • "In disagreement with this simple model, however, some components of these pathways have been implicated in many diverse processes. This is the case for bar-1/β-catenin, which is required for P12 cell fate specification [53] and for D-type axon guidance (this work), as well as for mig-5/Dsh, which is used during QL neuroblast migration and P12 cell fate specification [54], B cell division [55], and by D-type axons (this work). It is thus likely that the particular developmental context of each cell, and not only the pathway that is recruited, influences the outcome of Wnt/Fz activation. "
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    ABSTRACT: Wnts are secreted glycoproteins that regulate diverse aspects of development, including cell proliferation, cell fate specification and differentiation. More recently, Wnts have been shown to direct axon guidance in vertebrates, flies and worms. However, little is known about the intracellular signaling pathways downstream of Wnts in axon guidance. Here we show that the posterior C. elegans Wnt protein LIN-44 repels the axons of the adjacent D-type motor neurons by activating its receptor LIN-17/Frizzled on the neurons. Moreover, mutations in mig-5/Disheveled, gsk-3, pry-1/Axin, bar-1/beta-catenin and pop-1/TCF, also cause disrupted D-type axon pathfinding. Reduced BAR-1/beta-catenin activity in D-type axons leads to undergrowth of axons, while stabilization of BAR-1/beta-catenin in a lin-23/SCF(beta-TrCP) mutant results in an overextension phenotype. Together, our data provide evidence that Wnt-mediated axon guidance can be transduced through a beta-catenin-dependent pathway.
    Full-text · Article · Feb 2009 · PLoS ONE
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    • "In the first larval stage (L1), the left Q neuroblast (QL) and its descendents migrate posteriorly, while the right Q neuroblast (QR) and its descendents migrate anteriorly (Figure 1A; Sulston and Horvitz, 1977). Loss of the Wnt EGL-20, the Frizzled receptors MIG-1 or LIN-17, the Dishevelled MIG-5, the b-catenin BAR-1, or the TCF transcription factor POP-1 cause the QL descendents to migrate anteriorly (Harris et al., 1996; Herman, 2001; Maloof et al., 1999; Walston et al., 2006). "
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    ABSTRACT: While endocytosis can regulate morphogen distribution, its precise role in shaping these gradients is unclear. Even more enigmatic is the role of retromer, a complex that shuttles proteins between endosomes and the Golgi apparatus, in Wnt gradient formation. Here we report that DPY-23, the C. elegans mu subunit of the clathrin adaptor AP-2 that mediates the endocytosis of membrane proteins, regulates Wnt function. dpy-23 mutants display Wnt phenotypes, including defects in neuronal migration, neuronal polarity, and asymmetric cell division. DPY-23 acts in Wnt-expressing cells to promote these processes. MIG-14, the C. elegans homolog of the Wnt-secretion factor Wntless, also acts in these cells to control Wnt function. In dpy-23 mutants, MIG-14 accumulates at or near the plasma membrane. By contrast, MIG-14 accumulates in intracellular compartments in retromer mutants. Based on our observations, we propose that intracellular trafficking of MIG-14 by AP-2 and retromer plays an important role in Wnt secretion.
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