RNA localization in neural stem cells during cortical development

Duke University, Durham NC

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Abstract

Project Summary: The objectives of this pre-doctoral fellowship are twofold: first, to enhance the students training into an independent researcher in the field of neural development; and second, to investigate post-transcriptional regulation in radial glial cells during cortical development. Towards the first objective, we have designed a training plan to provide scientific and professional training for the applicant to achieve her goal of becoming a research scientist. This plan will be implemented under the guidance of sponsors with expertise in mouse cortical development and RNA biology. Towards the second objective, we will explore the role of asymmetric RNA localization in radial glial cells during cortical development. Precise regulation of radial glial cells is critical for generating a properly sized and organized brain, whereas dysregulation leads to malformations of the cerebral cortex, like microcephaly, and intellectual disabilities. Understanding the basic biology of radial glial cells will help advance our understanding of processes that go awry in neurodevelopmental disorders. The applicant will investigate regulation of radial glial cell function through the unique lens of RNA localization and local translation. This proposal will focus specifically on the mRNA of a critical mammalian brain size regulator ? Cyclin D2. Cyclin D2 is proposed to function in the nucleus to drive cell cycle progression. Surprisingly, its mRNA is localized to a distal subcellular compartment of radial glial cells (the basal endfoot) located hundreds of microns away from the nucleus. It remains unclear whether asymmetric localization of Cyclin D2 is critical for its function in radial glial cells. The primary goals of this proposal are to characterize the translational regulation and behavior of CyclinD2 protein in radial glial endfeet. To achieve these goals, the applicant will employ a combination of embryological manipulations, molecular RNA techniques, live confocal microscopy, and proteomics. Aim1 will elucidate extracellular signaling factors that influence translation in radial glial endfeet. Aim2 will characterize the behavior, including transport dynamics and protein interactions, of CyclinD2 in endfeet. These studies are important for advancing our limited knowledge of how the endfoot compartment influences radial glial functions during development. Further, we anticipate this work will uncover novel mechanisms of regulating radial glial cells through mRNA localization. Finally, this work will inform us of the role of CyclinD2 protein in endfeet, which may help to explain its influence over brain size.