The Translational Regulatory Mechanisms of Neural Precursor Cell Maintenance and Differentiation

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In mammals, neural stem/precursor cells (NPCs) give rise to billions of neurons to build the brain. To ensure the appropriate neurogenesis the balance between NPC maintenance and differentiation is tightly controlled. The long-term objective of my research program is to understand gene regulatory mechanisms that underlie NPC maintenance and differentiation. In the past few decades, considerable efforts have been directed towards understanding transcriptional mechanisms that regulate NPCs. Nevertheless, how other layers of gene regulation control NPCs remains largely unexplored. Using the developing mouse cortex as our model system, we have recently found that many genes that promote differentiation are transcribed ubiquitously in cortical NPCs, but those transcripts are not translated. Thus, translational regulation plays a critical role in NPC maintenance and differentiation, though the specific mechanisms are poorly understood. Therefore, my short-term objective is focused on understanding translational control mechanisms. We identified a group of translational repression complexes that contain the core repressor protein 4E-T. The complexes play a key role in maintaining the stem cell state of cortical NPCs. In searching the other components of the 4E-T complexes, we identified many target-specific RNA-binding proteins that interact with 4E-T in NPCs, such as the cytoplasmic polyadenylation element binding protein 4 (CPEB4). We hypothesize that by forming complexes with distinct target-specific RNA-binding proteins, 4E-T controls different subsets of mRNAs to regulate NPC maintenance and differentiation. In this proposal, we will use CPEB4 as an example to illustrate how in the long term we will dissect the role of various RNA-binding proteins in NPC homeostasis. In three specific aims, we will: 1) Determine the roles of RNA-binding proteins in NPC maintenance and differentiation both in vitro and in vivo, by applying loss- and gain-of-function approaches; 2) Identify target mRNAs for the RNA-binding proteins, using both genome-wide and candidate-gene approaches; and 3) Characterize the interactions between 4E-T and RNA-binding proteins to assess how the different complexes regulate NPC homeostasis. The proposed studies will elucidate translational control mechanisms of NPC homeostasis and serve as a foundation for my long-term research goal to fully reveal the gene regulatory landscape in NPCs. By advancing our understanding of how gene expression is controlled at multiple levels to coordinate stem cell homeostasis, my research will spark new technologies for stem cell manufacturing and tissue engineering applications. Importantly, by learning state-of-the-art techniques for high-resolution imaging, gene regulation, and stem cell biology, HQP in my research program will develop professional skills for a career within or outside academia.