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.
Highlights
Alternative splicing (AS) is one crucial step of gene expression that must be tightly regulated during neurodevelopment
To determine the precise timing of developmental splicing changes, we profiled the transcriptome of mouse cortices by RNA-seq at nine time points: embryonic day 14.5 (E14.5), E16.5, postnatal day 4 (P4), P7, P17, P30, 4 months, and 21 months (Supplementary Fig. 1a, b and Supplementary Dataset 1)
These results strongly suggest that the four RNA-binding proteins (RBPs) families are key players of the developmental splicing program to specify the precise timing, lack of significant contribution from additional RBPs to the model performance could reflect the redundancy of these features for prediction
Summary
Alternative splicing (AS) is one crucial step of gene expression that must be tightly regulated during neurodevelopment. The limited sampling resolution, incomplete coverage of developmental stages, and the scope of analysis have impeded previous studies to uncover the precise timing of developmental splicing switches, the key regulatory signals, and the link to developmental cellular processes To address these issues, here we systematically investigate the organization of the developmental splicing profiles in a large panel of developing mouse cortical tissues and different subtypes of neurons isolated in situ, as well as neurons differentiated in vitro from ESCs. In combination with integrative modeling of RNA-regulatory networks[23,24], this approach allows us to dissect the underlying regulatory mechanisms that control the splicing program at specific neuronal maturation stages and diverse neuronal subtypes in the central and peripheral nervous system
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