The Caenorhabditis elegans gene unc-76 and its human homologs define a new gene family involved in axonal outgrowth and fasciculation

Abstract

The gene unc-76 (unc, uncoordinated) is necessary for normal axonal bundling and elongation within axon bundles in the nematode Caenorhabditis elegans. The UNC-76 protein and two human homologs identified as expressed sequence tags are not similar to previously characterized proteins and thus represent a new protein family. At least one of these human homologs can function in C. elegans, suggesting that it, like UNC-76, acts in axonal outgrowth. We propose that the UNC-76 protein, which is found in cell bodies and processes of all neurons throughout development, either has a structural role in the formation and maintenance of axonal bundles or transduces signals to the intracellular machinery that regulates axonal extension and adhesion.Axons in developing nervous systems navigate through a varied set of extracellular environments to reach their targets. Most axons grow along other axons for much of their lengths, and the association of axons in specific bundles, or fascicles, is likely to play a major role in nervous system assembly. Although many cell-surface proteins involved in fascicle formation have been identified (1), relatively little is known about the intracellular mechanisms by which surface interactions lead to the elongation of axons specifically along other axonal surfaces.Genetic screens for fasciculation-defective mutants can, in principle, identify molecules necessary for fasciculation without presuppositions as to their biochemical nature or subcellular localization. Analysis of strains of the nematode Caenorhabditis elegans with mutations causing locomotory defects (uncoordinated or unc mutants) has revealed a group of three genes that, when mutant, affect the growth of axons in fascicles, but not along nonneuronal substrates (cells of the lateral hypodermis and the overlying basement membrane; refs. 2-4). Mutations in this fascicle-specific group of genes, unc-34, unc-71, and unc-76, cause two types of defects: many axons fail to extend fully within the axon bundles of the dorsal and ventral nerve cords, and many fail to remain in their normal fascicles (2-4). The best-characterized example of these defects is provided by the axons of the left and right hermaphrodite-specific neuron (HSN) motor neurons. In fascicle-specific mutants, these axons end prematurely within the left and right fascicles of the ventral nerve cord, respectively, and they often fail to remain on opposite sides of the cord (refs. 3, 4; L.B. and H.R.H., unpublished observations). If a second mutation causes the HSN axons to be rerouted along a lateral process tract instead of the ventral nerve cord, the axons in these mutants grow to their normal lengths, indicating that unc-34 and unc-76 affect the interaction of these axons with the ventral cord environment rather than the ability of the HSN axons to grow beyond a certain length (4).Among the mutants with fascicle-specific defects, unc-76 mutant animals have the most severe abnormalities in locomotion and HSN outgrowth (3, 4). To understand the basis of these...

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