Shaping human brain development and vulnerability through alternative splicing

Abstract

Alternative splicing contributes to shaping lineage-specific gene expression and phenotypes. In this issue of Cell Genomics, Recinos, Bao, Wang, et al.¹ report that the balance between splicing isoforms of the microtubule-associated protein Tau in the brain is differentially regulated among primates by the RNA-binding protein MBNL2, with consequences for protein aggregation and neurodegeneration in humans.

Figure 1

Regulation and impact of MAPT exon 10 splicing MAPT exon 10 inclusion levels have been proposed to depend on a stem-loop structure that sequesters the 5′ splice site and on the activity of muscleblind-like (MBNL) protein-binding sites in the downstream intron that promotes exon inclusion. Recinos, Bao, Wang, et al. show that differences in MAPT exon 10 inclusion in the brains of different mammalian (particularly primate) species can be explained, at least in part, by the number and affinity of MBNL-binding sites within intron 10. Steric hindrance of these binding sites (e.g., by competitive binding of CRISPR-dCas13d/gRNAs) promotes exon 10 skipping and might be used as a potential therapy to counteract excessive exon 10 inclusion observed in frontotemporal lobar degeneration (FTLD) due to stem-loop-disrupting mutations.