Precise temporal regulation of alternative splicing during neural development

Abstract

Alternative splicing (AS) is one crucial step of gene expression that must be tightly regulated during neurodevelopment. However, the precise timing of developmental splicing switches and the underlying regulatory mechanisms are poorly understood. Here we systematically analyze the temporal regulation of AS in a large number of transcriptome profiles of developing mouse cortices, in vivo purified neuronal subtypes, and neurons differentiated in vitro. Our analysis reveals early-switch and late-switch exons in genes with distinct functions, and these switches accurately define neuronal maturation stages. Integrative modeling suggests that these switches are under direct and combinatorial regulation by distinct sets of neuronal RNA-binding proteins including Nova, Rbfox, Mbnl, and Ptbp. Surprisingly, various neuronal subtypes in the sensory systems lack Nova and/or Rbfox expression. These neurons retain the “immature” splicing program in early-switch exons, affecting numerous synaptic genes. These results provide new insights into the organization and regulation of the neurodevelopmental transcriptome.

Isoform cell type specificity in the mouse primary motor cortex

“…Transcriptional and post-transcriptional control of individual isoforms of genes is crucial for neuronal differentiation [1][2][3][4][5] , and isoforms of genes have been shown to be specific to cell-types in mouse and human brains [6][7][8][9][10][11] . It is therefore not surprising that dysregulation of splicing has been shown to be associated with several neurodevelopmental and neuropsychiatric diseases 3,12,13 .…”

Secondary motifs enable concentration-dependent regulation by Rbfox family proteins

“…Rbfox1 was identified in 1994 as the genomic locus feminizing on X (fox-1) in C. elegans; it was subsequently shown that the encoded protein peaks in expression in larval developmental stages and controls sex determination by repressing the dosage compensation factor xol-1 post-transcriptionally 1,2 . Mammalian Rbfox1 (A2BP1) and its paralogs Rbfox2 (RBM9) and Rbfox3 (NeuN) are highly expressed in heart, skeletal muscle, and in the adult brain, with a characteristic spike in expression in late neuronal development [3][4][5][6] . While Rbfox proteins are predominantly nuclear, where they regulate pre-mRNA splicing, some isoforms are also expressed in the cytoplasm, where they regulate RNA stability 7 .…”

dSreg: A bayesian model to integrate changes in splicing and RNA binding protein activity

“…Alternative mRNAs may be generated from the same gene by inclusion or skipping of a particular exon in the mature transcript, in a process known as alternative splicing (AS) (19,36). There is evidence of AS for most mammalian genes (35,38) and of widespread changes of AS patterns throughout brain and heart development (4,5,15,18,23,42,43,56). Defects in mRNA processing of some specific genes often lead to disease (5,26,27) and have been associated with complex neurological disorders, such as autistic syndrome (23,28,42,55), and cancer (12,49).…”