Precise temporal regulation of alternative splicing during neural development

Sebastien M. Weyn-Vanhentenryck, Huijuan Feng, Dmytro Ustianenko, Rachel Duffié, Qinghong Yan, Martin Jacko, Jose C. Martinez, Marianne Goodwin, Xuegong Zhang, Ulrich Hengst, Stavros Lomvardas, Maurice S. Swanson and Chaolin Zhang ()
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Sebastien M. Weyn-Vanhentenryck: Columbia University
Huijuan Feng: Columbia University
Dmytro Ustianenko: Columbia University
Rachel Duffié: Columbia University
Qinghong Yan: Columbia University
Martin Jacko: Columbia University
Jose C. Martinez: Columbia University
Marianne Goodwin: University of Florida, College of Medicine
Xuegong Zhang: Tsinghua University
Ulrich Hengst: Columbia University
Stavros Lomvardas: Columbia University
Maurice S. Swanson: University of Florida, College of Medicine
Chaolin Zhang: Columbia University

Nature Communications, 2018, vol. 9, issue 1, 1-17

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-04559-0

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