Precise temporal regulation of alternative splicing during neural development

Abstract

Alternative splicing (AS) is a crucial step of gene expression that must be tightly controlled, but the precise timing of dynamic splicing switches during neural development and the underlying regulatory mechanisms are poorly understood. Here we systematically analyzed 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 revealed early-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.

ASCOT identifies key regulators of neuronal subtype-specific splicing

“…3b). High levels of Ptbp1 repress many exons, and downregulation of Ptbp1 accompanied by an upregulation of Ptbp2 is an important prerequisite for neuronal splicing 36,37,[51][52][53][54][55][56][57][58][59][60] . We hypothesized that certain RBPs, acting as splicing enhancers, could be selectively expressed in rods to mediate rod-specific splicing.…”

“…The vertebrate nervous system derives much of its transcriptomic and proteomic diversity from highly specific alternative splicing patterns that are not present elsewhere in the body 34 . Many neuronal subtypes, such as rod photoreceptors, also exhibit alternative exons that are only detected in that specific cell type [35][36][37][38] . Photoreceptors are cells within the retina that sense light and transduce this information for the brain.…”

Alternative splicing programming of axon formation

“…The diversity of brain cell types may be a factor. Recent studies show most alternative splicing in the brain originates from neuronal cells rather than glia, epithelial cells, or other non‐neuronal cells (Weyn‐Vanhentenryck et al, ). Another contributor can be numerous neuronal subtypes that may exhibit distinct splicing patterns to meet their morphological and functional diversity.…”

Loss of MBNL1 induces RNA misprocessing in the thymus and peripheral blood

“…While transcriptional regulation has been shown to play a vital role in both thymic organogenesis and T cell development 4 , co-/post-transcriptional events have also been implicated in thymocyte differentiation 5,6 . Indeed, alternative splicing (AS) adds another layer of complexity and diversity for developmental and tissue-restricted expression and splicing patterns for many gene transcripts that shift during development and aging [7][8][9] .…”