C. elegans CARMIL negatively regulates UNC-73/Trio function during neuronal development.
Whereas many molecules that promote cell and axonal growth cone migrations have been identified, few are known to inhibit these processes. In genetic screens designed to identify molecules that negatively regulate such migrations, we identified CRML-1, the C. elegans homolog of CARMIL. Although mammalian CARMIL acts to promote the migration of glioblastoma cells, we found that CRML-1 acts as a negative regulator of neuronal cell and axon growth cone migrations. Genetic evidence indicates that CRML-1 regulates these migrations by inhibiting the Rac GEF activity of UNC-73, a homolog of the Rac and Rho GEF Trio. The antagonistic effects of CRML-1 and UNC-73 can control the direction of growth cone migration by regulating the levels of the SAX-3 (a Robo homolog) guidance receptor. Consistent with the hypothesis that CRML-1 negatively regulates UNC-73 activity, these two proteins form a complex in vivo. Based on these observations, we propose a role for CRML-1 as a novel regulator of cell and axon migrations that acts through inhibition of Rac signaling.
Vanderzalm
Pamela J
PJ
Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA.
Pandey
Amita
A
Hurwitz
Michael E
ME
Bloom
Laird
L
Horvitz
H Robert
HR
Garriga
Gian
G
D000595:Amino Acid Sequence; D000818:Animals; D030801:Animals, Genetically Modified; D001483:Base Sequence; D017173:Caenorhabditis elegans / Q000235:genetics / Q000254:growth & development* / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002465:Cell Movement; D003001:Cloning, Molecular; D017931:DNA Primers / Q000235:genetics; D015536:Down-Regulation; D018507:Gene Expression Regulation, Developmental; D017238:Genes, Helminth; D008959:Models, Neurological; D008969:Molecular Sequence Data; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D055495:Neurogenesis / Q000235:genetics / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D020744:rac GTP-Binding Proteins / Q000378:metabolism; D000097905:Roundabout Proteins
D029742:Caenorhabditis elegans Proteins; D017931:DNA Primers; D009419:Nerve Tissue Proteins; D011971:Receptors, Immunologic; D020744:rac GTP-Binding Proteins; D000097905:Roundabout Proteins; C111263:UNC-73 protein, C elegans; C541355:crml-1 protein, C elegans