title: The UNC-73/Trio RhoGEF-2 domain is required in separate isoforms for the regulation of pharynx pumping and normal neurotransmission in C. elegans.
abstract: In both Caenorhabditis elegans and Drosophila, UNC-73/Trio functions in axon guidance by signaling through the Rac GTPase to regulate cytoskeletal rearrangements necessary for growth cone migrations. Here, we show that the complex C. elegans unc-73 gene encodes at least eight differentially expressed UNC-73 intracellular protein isoforms. Previously reported mutations affecting UNC-73 isoforms encoding the Rac-specific RhoGEF-1 domain cause uncoordinated movement, correlating with defects in axon guidance. Mutations in isoforms encoding the Rho-specific RhoGEF-2 domain, which we describe here, result in L1 stage larval lethality with no associated axon guidance defects. Isoform-specific rescue experiments reveal separate functions for the various RhoGEF-2-containing UNC-73 isoforms, which would not likely be discovered by conventional genetic screening. UNC-73 D1 and D2 appear to function redundantly in pharynx muscle to regulate the rate and strength of pharynx pumping, and in the HSN neurons and vulval muscles to control egg laying. Isoforms C1, C2, E, and F act redundantly within the nervous system to regulate the speed of locomotion. The multiple UNC-73 isoforms containing Rac- and Rho-specific RhoGEF domains therefore have distinct physiological functions. In addition to its previously identified role involving RhoGEF-1 in migrating cells and growth cones, our data indicate that UNC-73 signals through RhoGEF-2 to regulate pharynx and vulva musculature and to modulate synaptic neurotransmission.
authors.affiliation: Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada.
authors.forename: Robert
authors.initials: R
authors.lastname: Steven
authors.forename: Lijia
authors.initials: L
authors.lastname: Zhang
authors.forename: Joseph
authors.initials: J
authors.lastname: Culotti
authors.forename: Tony
authors.initials: T
authors.lastname: Pawson
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D005260:Female; D015870:Gene Expression; D020662:Guanine Nucleotide Exchange Factors / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D008297:Male; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D010058:Oviposition / Q000502:physiology; D010614:Pharynx / Q000502:physiology; D010641:Phenotype; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D017434:Protein Structure, Tertiary; D064067:Rho Guanine Nucleotide Exchange Factors; D017384:Sequence Deletion; D009435:Synaptic Transmission / Q000502:physiology; D014844:Vulva / Q000502:physiology
chemical_list: D029742:Caenorhabditis elegans Proteins; D020662:Guanine Nucleotide Exchange Factors; D009419:Nerve Tissue Proteins; D020033:Protein Isoforms; D064067:Rho Guanine Nucleotide Exchange Factors; C111263:UNC-73 protein, C elegans