In C. elegans, all 302 neurons are generated by asymmetric cell division. To investigate the mechanisms underlying asymmetric neuroblast division we have focused on the lineage that generates PHA, a sensory neuron in the tail. In wild type, the ABpl/rpppa blast cell divides asymmetrically to generate distinct anterior and posterior daughter cells. The anterior daughter cell divides further to produce five neurons, one of which is PHA. The posterior daughter cell generates only non-neuronal cells. In mutants for dsh-2 and mom-5, which encode Dishevelled (Dsh) and Frizzled (Fz) homologs respectively, the posterior daughter cell is transformed into a second anterior-like cell. As a result there is a duplication of neurons normally descended from the anterior daughter cell, including PHA. We have shown that MOM-5/Fz regulates the distribution of DSH-2 protein to the cell cortex, suggesting that MOM-5 regulates asymmetric cell division by regulating DSH-2 localization. In other eukaryotes, Dsh and Fz are components of both canonical and non-canonical Wnt signaling pathways. Thus, our results indicate that cell signaling plays a role in asymmetric neuroblast division during C. elegans embryogenesis. In addition to division defects, loss of dsh-2 function also results in embryonic lethality due to ventral enclosure defects. We have evidence suggesting that the ventral enclosure defects may be a secondary consequence of earlier asymmetric cell division defects. Using cell-specific GFP reporters, we have identified numerous additional neuronal duplications and losses that are consistent with many additional division defects in dsh-2 mutants. In addition, expression of dsh-2 under the control of a neuronal-specific promoter (unc-119) results in partial rescue of the dsh-2 lethality while no rescue has been observed using a hypodermal-specific promoter (lin-26). Although the unc-119 construct appears to give some embryonic hypodermal expression, the lack of rescue using the lin-26 promoter strongly suggests that dsh-2 expression in neural lineages is at least partially necessary for ventral enclosure. To identify additional genes required for asymmetric neuroblast division, we performed a large-scale genetic screen to isolate suppressors of the dsh-2 lethality. In total, we isolated 86 suppressors, most of which also suppress asymmetric division defects in the PHA lineage. We are currently in the process of mapping and characterizing a subset of these suppressors.

Affiliations:
- Mol. Biology and Biochem., Simon Fraser University, Burnaby, BC, Canada
- Department of Zoology, University of WI-Madison, Madison, WI