VP16-ACTIVATION OF THE C-ELEGANS NEURAL SPECIFICATION TRANSCRIPTION FACTOR UNC-86 SUPPRESSES MUTATIONS IN DOWNSTREAM GENES AND CAUSES DEFECTS IN NEURAL MIGRATION AND AXON OUTGROWTH

The POU homeobox gene unc-86 specifies many neuroblast and neural fate s in the developing C. elegans nervous system. Genes regulated by unc- 86 are mostly unknown. Here we describe a genetic strategy for the ide ntification of downstream pathways regulated by unc-86. We activate UN C-86 transcription activity by inserting the VP16 activation domain in to an unc-86 genomic clone that bears all regulatory sequences necessa ry for normal expression in C. elegans. unc-86/VP16 complements unc-86 mutations in the specification of neuroblast and neural cell fates, b ut displays novel genetic activities: it can suppress non-null mutatio ns in the downstream genes mec-3 and mec-7 that are necessary for mech anosensory neuron differentiation and function. These data suggest tha t UNC-86/VP16 increases the expression of mec-3 and mec-7 to compensat e for the decreased activities of mutant MEC-3 or MEC-7 proteins. The suppression of mutations in downstream genes by an activated upstream transcription factor should be a general strategy for the identificati on of genes in transcriptional cascades. unc-86/VP16 also causes neura l migration and pathfinding defects and novel behavioral defects. Thus , increased or unregulated expression of genes downstream of unc-86 ca n confer novel neural phenotypes suggestive of roles for unc-86-regula ted genes in neural pathfinding and function. Genetic suppression of t hese unc-86/VP16 phenotypes may identify the unc-86 downstream genes t hat mediate these events in neurogenesis.