Dynamic control of cortical development and disease by mRNA stability

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Abstract Development of the cerebral cortex requires precise regulatory control to ensure genes are expressed in the correct cell types and at the proper developmental stages. Analyses of gene expression across cell types and development, have revealed extensive diversity in cellular transcriptomes. However, transcriptomic datasets only provide a static snapshot of gene expression. Transcript expression is influenced by a balance between rates of transcription and RNA degradation, yet the role of the latter in cortical development is poorly understood. The overall goal of this proposal is uncover how mRNA stability contributes to the dynamic nature of cellular transcriptomes across cortical development. First, we will elucidate, for the first time, the temporal landscape of mRNA stability during cortical development. We will use state-of-the-art SLAM-seq approaches to quantify mRNA stability across neural differentiation stages in both mouse and human models. These data will be interrogated to inform both cis and trans control of RNA degradation and to prioritize disease loci influenced by stability. Second, we will investigate requirements for components of the CCR4-NOT complex, a central regulator of RNA stability, in cortical development. Our preliminary data demonstrate the CNOT3 component is essential for cortical development. Thus, we will use knockdown approaches and rescue experiments to measure the extent to which CNOT3 controls cortical development as part of the CCR4-NOT complex. Further, as components of this complex are mutated in autism, we will investigate how these mutations impair cortical development. Upon completion, our studies will establish the first comprehensive repertoire of mRNAs that are dynamically regulated at the level of stability in mouse and human development. By investigating genetic requirements of RNA stability factors for corticogenesis, we will establish new paradigms for how cell fate is regulated in the nervous system and relevant for disease. Together, this will open up new research directions into the basis of molecular control of brain development and disease.