title: The Nesprin family member ANC-1 regulates synapse formation and axon termination by functioning in a pathway with RPM-1 and β-Catenin.
abstract: Mutations in Nesprin-1 and 2 (also called Syne-1 and 2) are associated with numerous diseases including autism, cerebellar ataxia, cancer, and Emery-Dreifuss muscular dystrophy. Nesprin-1 and 2 have conserved orthologs in flies and worms called MSP-300 and abnormal nuclear Anchorage 1 (ANC-1), respectively. The Nesprin protein family mediates nuclear and organelle anchorage and positioning. In the nervous system, the only known function of Nesprin-1 and 2 is in regulation of neurogenesis and neural migration. It remains unclear if Nesprin-1 and 2 regulate other functions in neurons. Using a proteomic approach in C. elegans, we have found that ANC-1 binds to the Regulator of Presynaptic Morphology 1 (RPM-1). RPM-1 is part of a conserved family of signaling molecules called Pam/Highwire/RPM-1 (PHR) proteins that are important regulators of neuronal development. We have found that ANC-1, like RPM-1, regulates axon termination and synapse formation. Our genetic analysis indicates that ANC-1 functions via the β-catenin BAR-1, and the ANC-1/BAR-1 pathway functions cell autonomously, downstream of RPM-1 to regulate neuronal development. Further, ANC-1 binding to the nucleus is required for its function in axon termination and synapse formation. We identify variable roles for four different Wnts (LIN-44, EGL-20, CWN-1 and CWN-2) that function through BAR-1 to regulate axon termination. Our study highlights an emerging, broad role for ANC-1 in neuronal development, and unveils a new and unexpected mechanism by which RPM-1 functions.
authors.affiliation: Department of Pharmacology, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors.forename: Erik D
authors.initials: ED
authors.lastname: Tulgren
authors.affiliation: Department of Neuroscience, The Scripps Research Institute - Florida, Jupiter, Florida, United States of America.
authors.forename: Shane M
authors.initials: SM
authors.lastname: Turgeon
authors.affiliation: Department of Neuroscience, The Scripps Research Institute - Florida, Jupiter, Florida, United States of America.
authors.forename: Karla J
authors.initials: KJ
authors.lastname: Opperman
authors.affiliation: Department of Neuroscience, The Scripps Research Institute - Florida, Jupiter, Florida, United States of America.
authors.forename: Brock
authors.initials: B
authors.lastname: Grill
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001369:Axons; D017173:Caenorhabditis elegans / Q000235:genetics / Q000254:growth & development; D029742:Caenorhabditis elegans Proteins / Q000235:genetics* / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics* / Q000378:metabolism; D008840:Microfilament Proteins / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D055495:Neurogenesis / Q000235:genetics*; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics* / Q000378:metabolism
chemical_list: C468285:ANC-1 protein, C elegans; D029742:Caenorhabditis elegans Proteins; D020662:Guanine Nucleotide Exchange Factors; D008840:Microfilament Proteins; C409634:RPM-1 protein, C elegans; D051176:beta Catenin