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.