SAM68 regulates neuronal activity-dependent alternative splicing of neurexin-1

Cell. 2011 Dec 23;147(7):1601-14. doi: 10.1016/j.cell.2011.11.028.

Abstract

The assembly of synapses and neuronal circuits relies on an array of molecular recognition events and their modification by neuronal activity. Neurexins are a highly polymorphic family of synaptic receptors diversified by extensive alternative splicing. Neurexin variants exhibit distinct isoform-specific biochemical interactions and synapse assembly functions, but the mechanisms governing splice isoform choice are not understood. We demonstrate that Nrxn1 alternative splicing is temporally and spatially controlled in the mouse brain. Neuronal activity triggers a shift in Nrxn1 splice isoform choice via calcium/calmodulin-dependent kinase IV signaling. Activity-dependent alternative splicing of Nrxn1 requires the KH-domain RNA-binding protein SAM68 that associates with RNA response elements in the Nrxn1 pre-mRNA. Our findings uncover SAM68 as a key regulator of dynamic control of Nrxn1 molecular diversity and activity-dependent alternative splicing in the central nervous system.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Alternative Splicing*
  • Animals
  • Base Sequence
  • Cerebellum / cytology
  • Cerebellum / metabolism*
  • Humans
  • Mice
  • Mice, Knockout
  • Molecular Sequence Data
  • Neural Cell Adhesion Molecules / metabolism*
  • Neurons / metabolism
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism*
  • Response Elements

Substances

  • Adaptor Proteins, Signal Transducing
  • Khdrbs1 protein, mouse
  • Neural Cell Adhesion Molecules
  • Nrxn1 protein, mouse
  • RNA-Binding Proteins