This goal of this R21 proposal is to uncover post-transcriptional mechanisms important for neural progenitors of the developing brain, by focusing on the RNA binding protein, Rbm8a. RBM8A copy number variations are associated with intellectual disability, autism, microcephaly and macrocephaly. RBM8A mutations cause TAR syndrome, a rare blood and bone disorder which can also present with neurodevelopmental deficits. These neurodevelopmental pathologies can arise from aberrant neurogenesis of the cerebral cortex, in which neurons are produced from proliferating neural progenitors. Indeed, our lab has discovered that neural progenitor- specific Rbm8a haploinsufficiency in mice disrupts progenitor function and neurogenesis, which ultimately causes microcephaly. Rbm8a, together with Magoh and Eif4a3, form the exon junction complex, which binds spliced mRNAs to mediate key aspects of mRNA metabolism including translation. Together these findings demonstrate Rbm8a may influence disease by disrupting neurogenesis. However, our understanding of molecular mechanisms by which Rbm8a impacts brain development is limited to just a few candidates. In this proposal, we will test the central hypothesis that Rbm8a binds to and promotes translation of transcripts relevant for neural progenitor proliferation. First we will identify direct targets of Rbm8a in neuroepithelial progenitors, using a novel RNA immunoprecipitation-based approach in vivo. Second, we will use biochemical approaches to discover Rbm8a translational targets in neuroepithelial progenitors. Our proposal is built upon strong preliminary data, including the discovery of transcriptome-wide changes in Rbm8a hapoloinsufficient neuroepithelial progenitors. Successfully completed, these aims will provide new insights into how neural progenitors regulate fate decisions in the developing brain under both normal and pathological settings. Because RBM8A mutation is associated with neurodevelopmental disorders, these studies promise to provide important molecular insights into how mutations in this gene influence disease pathology.
This project will advance our understanding of the genetic regulation of neural stem cells, neurogenesis, and brain development. These processes are relevant to the etiology of neurodevelopmental disorders, such as microcephaly, and psychiatric disorders, such as autism. Therefore, this study may eventually help in the development of diagnostic and therapeutic options for broad neurological disorders.
|Mitchell, Caitlyn; Silver, Debra L (2017) Enhancing our brains: Genomic mechanisms underlying cortical evolution. Semin Cell Dev Biol :|