The role of the mRNA decay factor CNOT3 in cortical development

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ABSTRACT Proper spatial and temporal control of gene expression during development of the cerebral cortex is critical for the maintenance of neural progenitors and for neural differentiation. While transcriptional regulation has long been recognized as critical to the control of gene expression during cortical development, the contribution of RNA decay is less well understood. Despite this, mis-regulation regulation of gene expression at the post-transcriptional level is emerging as a major cause of neurodevelopmental diseases, including intellectual disability and autism. CNOT3, a regulator of mRNA stability, has recently been found to be mutated in a cohort of patients suffering from intellectual disability and autism. Additional studies have shown that CNOT3 regulates the stability of transcripts encoding proteins involved in cell cycle regulation and stem cell fate. Despite the links between Cnot3, mRNA degradation, neurodevelopmental disease, how Cnot3 contributes to brain development, and its key targets in this process, are unknown. I will address this knowledge gap using a Cre-lox conditional knockout mouse model to ablate Cnot3 expression in neural progenitors. Preliminary data indicates that at embryonic day (E)14.5 (approximately mid-neurogenesis), cKO mice exhibit microcephaly, apoptosis, and a reduction in the number of actively proliferating cells. In this proposal, I will build upon these observations and test the overall hypothesis that that CNOT3-mediated regulation of mRNA stability is required for proper cortical development. Aim 1 investigates the impact of Cnot3 disruption across corticogenesis, and uses live imaging approaches to monitor the requirements for CNOT3 in progenitor fate decisions. Aim 2 uses state-of-the-art technology to globally monitor mRNA stability in neural progenitors and assess the consequences of Cnot3 deletion on mRNA stability. These approaches will reveal previously uncharacterized role for CNOT3 in cortical development, while providing an unprecedented view of RNA stability during cortical development, and how its mis-regulation contributes to disease.