UCSF

The nervous system has an exceptionally complex morphology. Even in C. elegans, a relatively simple animal, its complexity and intricacy is impressive. Studies of the mechanisms through which this structure forms have focused on morphogens that direct the cell fate, polarity, and morphology of the individual cells. Genetic characterization indicated that the sax-3/ROBO axon guidance receptor is required for proper development of the major neuropil of the worm, the nerve ring, but its ligand slt-1/Slit had only minor effects. The absence of nerve ring defects in slt-1 mutants might be explained if there are other secreted axon guidance molecules function redundantly with slt-1.

A sensitized genetic screen in a slt-1 mutant background revealed mutants with defects in the development of the nerve ring. A number of mutants were obtained with nerve ring defects, some of which were more severe in a slt-1 mutant background. vab-3(Pax-6), vab-1(Eph receptor), vab-2(ephrin), unc-73(Trio), pig-1(MELK), and cwn-2(Wnt5), as well as a number of uncloned genes were determined to have nerve ring defects similar to those of sax-3.

The discovery that cwn-2 mutants have nerve ring defects implicated this Wnt gene in nervous system development. Wnts have been demonstrated to have many roles in development, ranging from cell fate determination to cell migration and axon guidance. This particular Wnt, cwn-2, was determined to be important for patterning the anterior nervous system of C. elegans. To understand signaling downstream of cwn-2, I examined mutants in genes that encode Wnt receptors. Such analysis identified nerve ring defects in cam-1 and cfz-2 mutants. cwn-2 was determined to act in the same pathway with the Ror-like cam-1 receptor. A wnt pathway involving the Frizzled gene cfz-2 acts in parallel to the cwn-2/cam-1(Ror) pathway for nerve ring development.

The cellular origin of the nerve ring defects was determined by finding that expression of either cam-1 or sax-3 receptor cDNAs in the SIA/SIB/SMD neurons rescued the corresponding mutant. cwn-2 and cam-1 mutants had unique axon guidance defects in the SIA/SIB/SMD neurons, suggesting that these neurons have a role in pioneering nerve ring development.