Guidance cues and their receptors direct cell and growth cone migrations by regulating cytoskeletal dynamics. Several signaling molecules that function downstream of guidance receptors to regulate actin have been described. We have found that three signaling molecules, UNC-34, the C. elegans homolog of Enabled, WAS-1, a homolog of the Wiskott-Aldrich Syndrome Protein (WASP), and DAB-1, a homolog of Disabled, act in parallel to regulate cell migrations in C. elegans. Drosophila Enabled (Ena) and its mouse homolog Mena function in axon outgrowth and fasciculation. The phenotypes of
unc-34 mutants show that this gene functions not only in these processes but also in cell migrations.
unc-34 null mutants are viable and display only partially penetrant defects in cell and growth cone migrations, suggesting the existance of parallel pathways in C. elegans that can compensate for the absence of UNC-34. By conducting RNAi experiments in an
unc-34 background, we have found that WAS-1 and DAB-1 act in parallel to UNC-34. Because both WASP and Ena have an EVH-1 domain at their N-termini and regulate actin assembly, we injected
was-1 RNA into wild-type and
unc-34 mutant animals. While
was-1(RNAi) animals appeared normal,
was-1(RNAi);
unc-34(null) animals died as embryos due to ventral enclosure defects. Injection of
was-1 RNA into a temperature-sensitive allele of
unc-34 resulted in temperature-dependent lethality. Injection into worms raised at 25, the restrictive temperature, resulted in embryonic lethality, while injected worms raised at 20 showed synthetic cell migration defects and partial lethality. These results show that UNC-34 and WAS-1 act in parallel pathways to control ventral enclosure and cell migration. A screen for mutations that result in synthetic lethal and migration defects in the
unc-34(ts) background has yielded several potential mutants. Disabled is a negative regulator of Ena in flies.
dab-1(RNAi) animals show defects in embryonic neuronal migrations, and injection of
dab-1 RNA into
unc-34(null) mutants results in enhanced migration defects. This result is different from the genetic evidence in Drosophila in which Disabled mutations suppress the Ena phenotype and suggests that
unc-34 and
dab-1 act in parallel pathways to regulate neuronal migrations in C. elegans.