A Highly Conserved Program of Neuronal Microexons Is Misregulated in Autistic Brains | Zendy

Manuel Irimia | Zendy; Robert J. Weatheritt | Zendy; Jonathan D. Ellis | Zendy; Neelroop Parikshak | Zendy; Thomas Gonatopoulos-Pournatzis | Zendy; Mariana Babor | Zendy; Mathieu Quesnel-Vallières | Zendy; Javier Tapial | Zendy; Bushra Raj | Zendy; Dave O’Hanlon | Zendy; Miriam BarriosRodiles | Zendy; Michael J.E. Sternberg | Zendy; Sabine P. Cordes | Zendy; Frederick P. Roth | Zendy; Jeffrey L. Wrana | Zendy; Daniel H. Geschwind | Zendy; Benjamin J. Blencowe | Zendy

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A Highly Conserved Program of Neuronal Microexons Is Misregulated in Autistic Brains

Author(s) -

Manuel Irimia,

Robert J. Weatheritt,

Jonathan D. Ellis,

Neelroop Parikshak,

Thomas Gonatopoulos-Pournatzis,

Mariana Babor,

Mathieu Quesnel-Vallières,

Javier Tapial,

Bushra Raj,

Dave O’Hanlon,

Miriam BarriosRodiles,

Michael J.E. Sternberg,

Sabine P. Cordes,

Frederick P. Roth,

Jeffrey L. Wrana,

Daniel H. Geschwind,

Benjamin J. Blencowe

Publication year - 2014

Publication title -

cell

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 26.304

H-Index - 776

eISSN - 1097-4172

pISSN - 0092-8674

DOI - 10.1016/j.cell.2014.11.035

Subject(s) - biology , neurogenesis , alternative splicing , rna splicing , autism , neuroscience , enhancer , computational biology , genetics , transcription factor , exon , gene , rna , psychology , developmental psychology

Alternative splicing (AS) generates vast transcriptomic and proteomic complexity. However, which of the myriad of detected AS events provide important biological functions is not well understood. Here, we define the largest program of functionally coordinated, neural-regulated AS described to date in mammals. Relative to all other types of AS within this program, 3-15 nucleotide "microexons" display the most striking evolutionary conservation and switch-like regulation. These microexons modulate the function of interaction domains of proteins involved in neurogenesis. Most neural microexons are regulated by the neuronal-specific splicing factor nSR100/SRRM4, through its binding to adjacent intronic enhancer motifs. Neural microexons are frequently misregulated in the brains of individuals with autism spectrum disorder, and this misregulation is associated with reduced levels of nSR100. The results thus reveal a highly conserved program of dynamic microexon regulation associated with the remodeling of protein-interaction networks during neurogenesis, the misregulation of which is linked to autism.

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