A TRPC5-regulated calcium signaling pathway controls dendrite patterning in the mammalian brain

Sidharth V. Puram, Antonio Riccio, Samir Koirala, Yoshiho Ikeuchi, Albert H. Kim, Gabriel Corfas, Azad Bonni

Research output: Contribution to journalArticlepeer-review

45 Scopus citations

Abstract

Department of Neurosurgery, Brigham and Women's Hospital, Children's Hospital, Boston, Massachusetts 02115, USA 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 cellautonomous 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/calmodulindependent kinase II b (CaMKIIb) as a critical effector of TRPC5 function in neurons. Remarkably, TRPC5 forms a complex specifically with CaMKIIb, but not the closely related kinase CaMKIIa, and thereby induces the CaMKIIb-dependent phosphorylation of the ubiquitin ligase Cdc20-APC at the centrosome. Accordingly, centrosomal CaMKIIb 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.

Original languageEnglish
Pages (from-to)2659-2673
Number of pages15
JournalGenes and Development
Volume25
Issue number24
DOIs
StatePublished - Dec 15 2011

Keywords

  • Cerebellar cortex
  • Dendrites
  • Protein kinase signaling

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