A long-standing question in biology has been to determine how the mammalian central nervous system (CNS) achieves its dramatic cellular complexity and connectivity. Notably, mechanisms increasing transcript diversity, particularly alternative splicing (AS) and RNA-editing, have critical roles in the mammalian CNS development and function. However, it is still unclear whether the crosstalk between these two processes constitutes an additional RNA-mediated regulatory layer contributing to the complex mammalian CNS. Thus, the main goal of NeuroASPECT is to determine the extent, dynamics and functional relevance of the crosstalk between AS and RNA-editing in the mammalian CNS. To tackle this general goal, I propose the following specific aims: 1) Elucidate the extent of co-regulation between AS and RNA-editing events in the CNS by building a comprehensive catalog of neural co-regulated AS-editing events in mammals and explore their evolutionary conservation in other vertebrates. 2) Assess the crosstalk between AS and RNA-editing in neural differentiation by analyzing transcriptomes of cells with impaired RNA-editing. 3) Characterize the functional impact of AS and RNA-editing crosstalk on mouse neurogenesis. I expect this work will uncover RNA networks established between AS and RNA-editing that are involved in shaping and regulating the CNS transcriptome. Moreover, it will also contribute to a better understanding of the biological functions and regulation of AS and RNA-editing, in both an independent and synergistic manner. In addition, the functional characterization of the AS-editing crosstalk could ultimately reveal alterations in which the lack of coordination between AS and RNA-editing can lead to the development of neurological disorders, thus offering potential targets for their treatment.
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