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

Abstract

Summary 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.

The landscape of human mutually exclusive splicing

“…In summary, the large core set of mammalian MXEs and the overall conservation of MXE clusters suggest that MXEs are considerably more conserved than cassette exons. This observation supports expectations from considering the encoded protein structures where MXEs are supposed to provide alternative sequences for conserved secondary structural elements, while cassette exons are on average considerably shorter and add flexibility to surface loops (Buljan et al , 2012; Ellis et al , 2012; Irimia et al , 2014). …”

“…In contrast to cassette exons and micro‐exons, which tend to be located in surface loops and intrinsically disordered regions instead of folded domains (Buljan et al , 2012; Ellis et al , 2012; Irimia et al , 2014), all MXEs, whose protein structures have been analysed, are embedded within folded structural domains as has been shown for, for example, DSCAM (Meijers et al , 2007), H2AFY (Kustatscher et al , 2005), the myosin motor domain (Kollmar & Hatje, 2014) and SLC25A3 (Tress et al , 2017a). As we have shown in the beginning, there is also a subset of 73 MXEs not showing any sequence homology (“annotated no similarity”).…”

Systematic discovery of regulated and conserved alternative exons in the mammalian brain reveals NMD modulating chromatin regulators

“…These exons are substantially smaller than constitutively spliced exons (85 nt vs. 114 nt, median), a feature known to be associated with regulated AS exons (4). In particular, 272 AS exons (including 117 newly discovered) have a size ≤ 27 nt, and such microexons have been shown recently to be particularly relevant to neurodevelopment (14,26,27). Therefore, deep survey of the transcriptome allows us to more than double the number of alternative exons that are likely functional.…”

Translational Research in Pediatrics IV: Solid Tissue Collection and Processing

“…233 The AFS has the practical limitation of its inability to assess each anatomic region separately, resulting in the development of an agonal stress rating system that evaluates the degree of stress based on gene expression data. 237 The agonal stress rating can reduce the number of false-positive findings by allowing a quantitative 113 • PPT1, caspase-3, cleaved-PARP, caspase-9, ROS, and SOD-2 113 • Infi ltrative glioma and gliosis 53 • EGFR 53 • Autism [197][198][199] • Neuronal microexons, 197 • Infantile X-linked dilated cardiomyopathy 200 • Saturated fatty acids, mitochondria structure 200 • Dilated cardiomyopathy and congenital heart disease 137…”