TY - JOUR
T1 - A highly conserved program of neuronal microexons is misregulated in autistic brains
AU - Irimia, Manuel
AU - Weatheritt, Robert J.
AU - Ellis, Jonathan D.
AU - Parikshak, Neelroop N.
AU - Gonatopoulos-Pournatzis, Thomas
AU - Babor, Mariana
AU - Quesnel-Vallières, Mathieu
AU - Tapial, Javier
AU - Raj, Bushra
AU - O'Hanlon, Dave
AU - Barrios-Rodiles, Miriam
AU - Sternberg, Michael J.E.
AU - Cordes, Sabine P.
AU - Roth, Frederick P.
AU - Wrana, Jeffrey L.
AU - Geschwind, Daniel H.
AU - Blencowe, Benjamin J.
N1 - Publisher Copyright:
© 2014 Elsevier Inc.
PY - 2014/12/18
Y1 - 2014/12/18
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84919928214&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2014.11.035
DO - 10.1016/j.cell.2014.11.035
M3 - Article
C2 - 25525873
AN - SCOPUS:84919928214
SN - 0092-8674
VL - 159
SP - 1511
EP - 1523
JO - Cell
JF - Cell
IS - 7
ER -