Project 2 Abstract Circuit formation in developing human brain involves sequential steps of: (i) cell fate specification, (ii) proliferation and regulation of precursor pool size, and (iii) migration of neural cells to their appropriate position to integrate into local circuits. Young interneurons (IN) and oligodendrocyte precursors (OPCs) persist as immature yet committed lineage cells for a protracted period of time during development, undergoing extensive migration and late differentiation before integration into/and myelination of neural circuits in human developing brain. This relatively long developmental time course means that they may be more vulnerable to neonatal injury. Our findings in the prior cycle of this program highlighted novel stromal interactions of OPCs and IN with blood vessels during development. We identified that OPCs use vasculature as a physical scaffold for migration in the developing CNS (Tsai Science 2016 PMC5472053), that OPCs drive white matter angiogenesis in mouse brain (Yuen Cell 2014 PMC4149873), and that migrating clusters of interneurons associate with the vasculature in the human brain (Paredes Science 2016 PMC5436574). However, very little is understood about the cellular and molecular mechanisms that underlie human OPC induced angiogenesis and IN perivascular migration, a phenomenon unique to human brain development. What are the cellular mechanisms that underlie angiogenesis directed by OL lineage in human brain? And how does the establishment of a vascular scaffold subsequently mediate and regulate IN sub-type migration? This project seeks to understand mechanisms underlying these processes in human neonatal brain. We will 1) evaluate factors involved in OPC interaction with endothelial tip cells as well as the morphological interaction, identify candidate angiogenic pathways and novel tip cell markers in human brain, and investigate dysfunction of OPC-tip cell interactions in human neonatal hypoxic injury. We will 2) determine a functional role for OPC-encoded Wnt and VEGF ligands in orchestrating endothelial tip cell angiogenesis and in resilience to hypoxic injury, and we will 3) identify the transcriptomic signature of vessel- associated migrating IN in human neonatal brain, and determine whether diversity of vessel associated versus non-vessel associated IN migration is a reflection on their developmental origin. Understanding the cellular mechanisms mediating OPC-mediated angiogenesis and IN vessel-associated migration in human brain will not only elucidate fundamental biological processes, but will provide insight into how dysregulation could occur in preterm birth and term hypoxia and provide perspective for the planning for therapeutic interventions.
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