Tata, MAJ; (2016) Vascular regulation of embryonic neurogenesis. Doctoral thesis , UCL (University College London).

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Abstract

Neural progenitor cells (NPCs) in the embryonic nervous system generate a large number and variety of neurons in a process known as neurogenesis. NPCs reside in a regulatory ‘niche’ that provides an extensive array of diverse signals, and loss of any one of these signals can deplete the pool of NPCs and therefore impair neural development. These niche signals are most commonly studied in the forebrain, where a complex array of cell divisions yields a set of diverse NPCs. In contrast, little is known on the role of niche signals in regulating the behaviour of NPCs in the hindbrain, the evolutionary oldest part of the brain that is essential for many vital bodily functions. In the adult brain, blood vessels and the vascular growth factor VEGF-A regulate the behaviour of neural stem cells (NSC). However, it is not known whether either also regulates hindbrain neurogenesis. For my PhD research, I have used the mouse embryo hindbrain as a model to examine the role of blood vessels and VEGF-A receptors in developmental neurogenesis. My studies have revealed that NPCs divide most actively during a period of extensive blood vessel growth in the hindbrain, that hindbrain NPCs reside within a well-vascularised germinal zone (GZ) and that they make physical contact with the GZ vasculature. To establish whether VEGF-A receptors or hindbrain blood vessels regulate the behaviour of hindbrain NPCs, I have analysed mouse embryos lacking the neurovascular cell surface receptor NRP1 in either the neural or endothelial lineages. I found that NRP1 regulates the proliferative behaviour of hindbrain NPCs through its role in promoting GZ vascularisation, but not as a receptor for VEGF-A in NPCs. I have further shown that GZ vasculature sustains the size of the NPC pool through the period of hindbrain neurogenesis and may do so by limiting the expression of pro-differentiation signals to set the pace of neurogenesis. Even though blood vessels are best know for their role in tissue oxygenation, my results also show that NRP1-dependent GZ vasculature does not regulate hindbrain NPC behaviour through its role in oxygenating the neuroepithelium. In conclusion, my results identify an essential role for blood vessels in regulating NPC behaviour in the embryonic hindbrain and have increased our understanding of the regulatory niche that orchestrates developmental neurogenesis.

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