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Mol Cell. 2016 Dec 15;64(6):1023-1034. doi: 10.1016/j.molcel.2016.11.033.

Misregulation of an Activity-Dependent Splicing Network as a Common Mechanism Underlying Autism Spectrum Disorders.

Author information

1
Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, ON M5G 1X5, Canada.
2
Department of Cell and Systems Biology, University of Toronto, Toronto, ON M5S 3G5, Canada.
3
Centre for Genomic Regulation, Barcelona Institute of Science and Technology (BIST), Dr. Aiguader 88, Barcelona 08003, Spain; Universitat Pompeu Fabra, Barcelona 08002, Spain.
4
Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada.
5
RNA Biology Laboratory, RIKEN, Wako, Saitama 351-0198, Japan.
6
Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada.
7
Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada. Electronic address: b.blencowe@utoronto.ca.
8
Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, ON M5G 1X5, Canada. Electronic address: cordes@lunenfeld.ca.

Abstract

A key challenge in understanding and ultimately treating autism is to identify common molecular mechanisms underlying this genetically heterogeneous disorder. Transcriptomic profiling of autistic brains has revealed correlated misregulation of the neuronal splicing regulator nSR100/SRRM4 and its target microexon splicing program in more than one-third of analyzed individuals. To investigate whether nSR100 misregulation is causally linked to autism, we generated mutant mice with reduced levels of this protein and its target splicing program. Remarkably, these mice display multiple autistic-like features, including altered social behaviors, synaptic density, and signaling. Moreover, increased neuronal activity, which is often associated with autism, results in a rapid decrease in nSR100 and splicing of microexons that significantly overlap those misregulated in autistic brains. Collectively, our results provide evidence that misregulation of an nSR100-dependent splicing network controlled by changes in neuronal activity is causally linked to a substantial fraction of autism cases.

KEYWORDS:

alternative splicing; autism spectrum disorder; microexons; nSR100/SRRM4; neuronal activity

PMID:
27984743
DOI:
10.1016/j.molcel.2016.11.033
[Indexed for MEDLINE]
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