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.