abstract axon guidance mechanisms in caenorhabditis elegans

ABSTRACT / RÉSUMÉ

Abstracts / Résumés

642

© 2000 NRC Canada

Axon guidance mechanisms in Caenorhabditiselegans

Joe Culotti, Bruce Nash, Hong Zheng, and Takehiro KawanoS.L. Research Institute of Mt. Sinai Hospital, Toronto, ON M5G 1X5 Canada, andMolecular and Medical Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada

An unusual TGF-beta, encoded by theunc-129gene ofC. elegans, regulates axon guidance along the dorsoventralaxis of the epidermis/neuroepithelium. This TGF-beta isexpressed in neurons and in the dorsal, but not ventral, bodymuscles. Promoter analysis suggests that it is the dorsalmuscle expression that is required for axon guidance.Ectopic expression of UNC-129 in both sets of body mus-cles using a myosin:unc-129(+) transgene induces axonguidance defects in otherwise wild-type animals.

This UNC-129 axon guidance system works in parallel withthe better known UNC-6/netrin axon guidance system, whichalso guides axons along the dorsoventral axis ofC. elegans.Interestingly, although mutations inunc-6 and the genes thatencode its receptors,unc-5 and unc-40, also affectdistal tipcell (DTC) migrations along the dorsoventral axis,unc-129mutations do not. However, whenunc-129 is expressed inboth sets of muscles, it induces DTC migration defects likethose observed inunc-5,-6,-40mutants. This suggests thatUNC-129 normally does have a minimal redundant effect onDTC migrations, but this effect is masked by UNC-5, -6,and -40 and perhaps by other mechanisms that act in parallelwith it.

Mutations in unc-130, which encodes a winged helixtranscription factor, mimic the phenotypes obtained withthe myosin:unc-129transgene.unc-130mutants have mildaxon guidance defects, are mildly uncoordinated, and have

DTC migration defects like those observed inunc-5,-6,-40mutants. The reason for this phenotype is apparent from theobservation thatunc-129reporters are expressed in both setsof muscles in anunc-130 mutant, whereas expression ofunc-5,-6, and-40 appear roughly normal in this mutant. Thissuggests that UNC-130 normally represses UNC-129 expres-sion in the ventral body muscles, a model that fits thephenotypic mimicry of the myosin:unc-129transgenics. Thismodel also fits the results ofunc-129; unc-130double mu-tant analysis. These double mutants have significantly fewerDTC migration defects than theunc-130mutants, suggestingthat the absence ofunc-129function is epistatic to the ab-sence ofunc-130function, as it should be if UNC-130 nor-mally inhibits UNC-129 expression.

We do not yet know if UNC-129 is acting directly as anaxon and cell migration guidance cue or whether it inducesthe epidermis to form a yet to be discovered cue. TheUNC-129 TGF-beta does not act through the classical type Iand type II receptors inC. elegansnor does it appear to re-quire Smad function. A genetic screen for UNC-129 signalingcomponents and their eventual molecular characterizationmay, therefore, identify novel TGF-beta signaling mecha-nisms involved in axon guidance. The ability ofunc-129mu-tations to suppressunc-130mutant DTC migrations providesa paradigm for identifying other components of the UNC-129signaling cascade.