title: 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.
abstract: The POU homeobox gene unc-86 specifies many neuroblast and neural fates in the developing C. elegans nervous system. Genes regulated by unc-86 are mostly unknown. Here we describe a genetic strategy for the identification of downstream pathways regulated by unc-86. We activate UNC-86 transcription activity by inserting the VP16 activation domain into an unc-86 genomic clone that bears all regulatory sequences necessary for normal expression in C. elegans. unc-86/VP16 complements unc-86 mutations in the specification of neuroblast and neural cell fates, but displays novel genetic activities: it can suppress non-null mutations in the downstream genes mec-3 and mec-7 that are necessary for mechanosensory neuron differentiation and function. These data suggest that UNC-86/VP16 increases the expression of mec-3 and mec-7 to compensate 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 identification of genes in transcriptional cascades. unc-86/VP16 also causes neural migration and pathfinding defects and novel behavioral defects. Thus, increased or unregulated expression of genes downstream of unc-86 can confer novel neural phenotypes suggestive of roles for unc-86-regulated genes in neural pathfinding and function. Genetic suppression of these unc-86/VP16 phenotypes may identify the unc-86 downstream genes that mediate these events in neurogenesis.
authors.affiliation: Department of Molecular Biology, Massachusetts General Hospital, Harvard Medical School, Boston 02114, USA.
authors.forename: J Y
authors.initials: JY
authors.lastname: Sze
authors.forename: Y
authors.initials: Y
authors.lastname: Liu
authors.forename: G
authors.initials: G
authors.lastname: Ruvkun
mesh_terms: D000818:Animals; D001369:Axons / Q000502:physiology*; D017173:Caenorhabditis elegans / Q000235:genetics / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins; D002454:Cell Differentiation; D005047:Etoposide / Q000494:pharmacology*; D018507:Gene Expression Regulation, Developmental; D017238:Genes, Helminth; D005816:Genetic Complementation Test; D015801:Helminth Proteins / Q000096:biosynthesis; D017405:Herpes Simplex Virus Protein Vmw65 / Q000096:biosynthesis*; D018398:Homeodomain Proteins / Q000378:metabolism*; D060850:LIM-Homeodomain Proteins; D009420:Nervous System / Q000166:cytology; D009424:Nervous System Physiological Phenomena; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D050809:POU Domain Factors; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D012045:Regulatory Sequences, Nucleic Acid; D014157:Transcription Factors / Q000096:biosynthesis / Q000378:metabolism*
chemical_list: D029742:Caenorhabditis elegans Proteins; D015801:Helminth Proteins; D017405:Herpes Simplex Virus Protein Vmw65; D018398:Homeodomain Proteins; D060850:LIM-Homeodomain Proteins; D050809:POU Domain Factors; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; C072005:mec-3 protein, C elegans; C081539:unc-86 protein, C elegans; D005047:Etoposide