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Post‐transcriptional regulation in corticogenesis: how RNA‐binding proteins help build the brain

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The cerebral cortex, the brain structure responsible for our higher cognitive functions, is built during embryonic development in a process called corticogenesis. During corticogenesis, neural stem cells generate distinct populations of progenitors and excitatory neurons. These new neurons migrate radially in the cortex, eventually forming neuronal layers and establishing synaptic connections with other neurons both within and outside the cortex. Perturbations to corticogenesis can result in severe neurodevelopmental disorders, thus emphasizing the need to better understand molecular regulation of brain development. Recent studies in both model organisms and humans have collectively highlighted roles for post‐transcriptional regulation in virtually all steps of corticogenesis. Genomic approaches have revealed global RNA changes associated with spatial and temporal regulation of cortical development. Additionally, genetic studies have uncovered RNA‐binding proteins (RBPs) critical for cell proliferation, differentiation, and migration within the developing neocortex. Many of these same RBPs play causal roles in neurodevelopmental pathologies. In the developing neocortex, RBPs influence diverse steps of mRNA metabolism, including splicing, stability, translation, and localization. With the advent of new technologies, researchers have begun to uncover key transcripts regulated by these RBPs. Given the complexity of the developing mammalian cortex, a major challenge for the future will be to understand how dynamic RNA regulation occurs within heterogeneous cell populations, across space and time. In sum, post‐transcriptional regulation has emerged as a critical mechanism for driving corticogenesis and exciting direction of future research. WIREs RNA 2015, 6:501–515. doi: 10.1002/wrna.1289 This article is categorized under: RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications RNA Export and Localization > RNA Localization RNA in Disease and Development > RNA in Development
Schematic representation of cortical development. Shown are three different progenitor populations (neuroepithelial cells, radial glial cells, and intermediate progenitors) and neurons (both migrating and differentiating). Progenitors residing within the VZ undergo self‐renewal divisions to generate new progenitors (curved arrow) as well as divisions to generate either neurons or progenitors (straight arrows). As corticogenesis proceeds, progenitors initially expand their population, shift to neuron, and intermediate progenitor production. Intermediate progenitors within the SVZ also generate neurons. Neurons migrate through the IZ to the CP to form layers of the cerebral cortex. MZ, marginal zone; CP, cortical plate; IZ, intermediate zone; SVZ, sub‐ventricular zone; VZ, ventricular zone
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Summary of known RNA‐binding proteins and the aspects of corticogenesis they regulate. Different aspects of neural progenitor function (cell cycle progression, cell fate decision, apoptosis) and neuronal function (migration, differentiation, maturation, apoptosis) are indicated along with the RBPs discussed in this review.
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Cartoon depicting various stages of mRNA life cycle when RBPs function. Different stages of posttranscriptional regulation are shown along with their nuclear‐cytoplasmic location. This review discusses roles for RNA‐binding proteins (shown as geometric shapes) in these various aspects of mRNA metabolism.
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RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications
RNA in Disease and Development > RNA in Development
RNA Export and Localization > RNA Localization

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