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RNA on the brain: emerging layers of post‐transcriptional regulation in cerebral cortex development

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Embryonic development is a critical period during which neurons of the brain are generated and organized. In the developing cerebral cortex, this requires complex processes of neural progenitor proliferation, neuronal differentiation, and migration. Each step relies upon highly regulated control of gene expression. In particular, RNA splicing, stability, localization, and translation have emerged as key post‐transcriptional regulatory nodes of mouse corticogenesis. Trans‐regulators of RNA metabolism, including microRNAs (miRs) and RNA‐binding proteins (RBPs), orchestrate diverse steps of cortical development. These trans‐factors function either individually or cooperatively to influence RNAs, often of similar classes, termed RNA regulons. New technological advances raise the potential for an increasingly sophisticated understanding of post‐transcriptional control in the developing neocortex. Many RNA‐binding factors are also implicated in neurodevelopmental diseases of the cortex. Therefore, elucidating how RBPs and miRs converge to influence mRNA expression in progenitors and neurons will give valuable insights into mechanisms of cortical development and disease.

Cartoon representation of RNA regulation in cortical development. (a) Cartoon representing embryonic brains from about E11.5 and E15.5, with a coronal section shown on the right. (b) Left, cartoon represented region indicated in (a), highlighting a radial glial cell (RGC, blue). Right, cartoon‐depicting roles for RBPs (hexagons) in alternative splicing in the nucleus, and translation, localization, and stability in the cytoplasm. microRNAs (red/black lines) work in the cytoplasm to degrade and translationally repress mRNAs.
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An example of a regulatory network in which microRNAs (miRs) and RNA‐binding proteins (RBPs) participate in neuronal differentiation and progenitor proliferation. miR‐124 is expressed at low levels in radial glial cells (RGCs), allowing for translation of polyprimidine tract‐binding variant (PTBP1). PTBP1 activity leads to production of a Ptbp2 splicing isoform fated for decay. Low levels of PTBP2 result in exclusion of neuron‐specific exons in targets, and ultimately repression of neuronal differentiation in progenitors. In the presence of miR‐124 in post‐mitotic neurons, PTBP1 is translationally repressed, allowing for splicing of functional PTBP2 and inclusion of neuron‐specific exons and differentiation. This illustrates how RBPs and miRNAs work co ordinately to post‐transcriptionally regulate mRNAs.
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Post‐transcriptional regulation during corticogenesis. (a) Three stages of corticogenesis discussed in this review. Early in corticogenesis, radial glial cells (RGCs, green) undergo symmetric, self‐renewing divisions to expand the progenitor pool. Later, RGCs divide asymmetrically to generate a more differentiated cell. RGCs generate excitatory neurons (blue) either directly or indirectly through intermediate progenitors. New born neurons polarize and migrate along the RGC scaffold to reach their final layer in the cortical plate. (b) Trans‐regulators implicated in each process. (c) Classes of target transcripts.
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