title: A TRPC5-regulated calcium signaling pathway controls dendrite patterning in the mammalian brain.
abstract: Transient receptor potential (TRP) channels have been implicated as sensors of diverse stimuli in mature neurons. However, developmental roles for TRP channels in the establishment of neuronal connectivity remain largely unexplored. Here, we identify an essential function for TRPC5, a member of the canonical TRP subfamily, in the regulation of dendrite patterning in the mammalian brain. Strikingly, TRPC5 knockout mice harbor long, highly branched granule neuron dendrites with impaired dendritic claw differentiation in the cerebellar cortex. In vivo RNAi analyses suggest that TRPC5 regulates dendrite morphogenesis in the cerebellar cortex in a cell-autonomous manner. Correlating with impaired dendrite patterning in the cerebellar cortex, behavioral analyses reveal that TRPC5 knockout mice have deficits in gait and motor coordination. Finally, we uncover the molecular basis of TRPC5's function in dendrite patterning. We identify the major protein kinase calcium/calmodulin-dependent kinase II β (CaMKIIβ) as a critical effector of TRPC5 function in neurons. Remarkably, TRPC5 forms a complex specifically with CaMKIIβ, but not the closely related kinase CaMKIIα, and thereby induces the CaMKIIβ-dependent phosphorylation of the ubiquitin ligase Cdc20-APC at the centrosome. Accordingly, centrosomal CaMKIIβ signaling mediates the ability of TRPC5 to regulate dendrite morphogenesis in neurons. Our findings define a novel function for TRPC5 that couples calcium signaling to a ubiquitin ligase pathway at the centrosome and thereby orchestrates dendrite patterning and connectivity in the brain.
authors.affiliation: Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Sidharth V
authors.initials: SV
authors.lastname: Puram
authors.forename: Antonio
authors.initials: A
authors.lastname: Riccio
authors.forename: Samir
authors.initials: S
authors.lastname: Koirala
authors.forename: Yoshiho
authors.initials: Y
authors.lastname: Ikeuchi
authors.forename: Albert H
authors.initials: AH
authors.lastname: Kim
authors.forename: Gabriel
authors.initials: G
authors.lastname: Corfas
authors.forename: Azad
authors.initials: A
authors.lastname: Bonni
mesh_terms: D000818:Animals; D020013:Calcium Signaling / Q000235:genetics*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D002478:Cells, Cultured; D018385:Centrosome / Q000378:metabolism; D002525:Cerebellar Cortex / Q000166:cytology* / Q000254:growth & development*; D003712:Dendrites / Q000502:physiology*; D055786:Gene Knockout Techniques; D008297:Male; D051379:Mice; D051381:Rats; D050052:TRPC Cation Channels / Q000235:genetics* / Q000378:metabolism*
chemical_list: D050052:TRPC Cation Channels; C112021:Trpc5 protein, mouse; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2