The Nesprin Family Member ANC-1 Regulates Synapse Formation and Axon Termination by Functioning in a Pathway with RPM-1 and β-Catenin

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. © 2014 tulgren et al.