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Molecular mechanisms controlling neurovascular patterning

Maden, C.; (2011) Molecular mechanisms controlling neurovascular patterning. Doctoral thesis , UCL (University College London). Green open access

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The vascular system delivers oxygen and nutrients to tissues throughout the developing organism, including the nervous system. Vice versa, the nervous system innervates resistance arteries to modulate vascular function. The two systems share several guidance cues and cell-­‐surface receptors. One receptor is neuropilin 1 (NRP1), which is present on blood vessels and neurons. The sympathetic nervous system is a neural crest cell (NCC)-­‐derived structure that innervates the heart and blood vessels to modulate heart rate and vasoconstriction. Semaphorin3A (SEMA3A) signals through NRP1 to pattern the axonal projections of sympathetic nerves. I show here that this signalling pathway also controls the earliest stage of sympathetic nervous system development -­‐ sympathetic NCC migration through the somites. Accordingly, sympathetic NCCs stray into ectopic territories and differentiate into sympathetic neurons in mice with disrupted NRP1/SEMA3A signalling. I also show that NRP2/SEMA3F signalling provides a backup pathway for NRP1/SEMA3A signalling in sympathetic NCC guidance. I further show defective sympathetic innervation of the heart and dorsal aorta in postnatal mice with disrupted NRP1/SEMA3A signalling and describe a previously unidentified role for NRP2 in sympathetic axon guidance. I found that the recently discovered SEMA3G does not play a part in sympathetic axon guidance to target arteries, despite its unique arterial expression. The alternative NRP1 ligand, a vascular endothelial growth factor isoform termed VEGF164, is essential for the sprouting of new blood vessels from existing ones in a process called angiogenesis. A large body of in vitro evidence suggests that heparan sulphate proteoglycans (HSPGs) are required for VEGF164 -­‐driven angiogenesis by promoting its interaction with its receptors VEGFR1, VEGFR2 and NRP1. In vivo data supporting the idea that HSPGs are essential for angiogenesis, however, are sparse. I here found that mouse embryos lacking enzymes required for the sulphation of HSPGs, or lacking enzymes essential for HSPG production in specific cells, had no obvious vascular branching defects in the hindbrain and do not phenocopy mutants lacking VEGF164. These observations suggest that HSPGs are not essential for VEGF164-­‐driven angiogenesis. In contrast, I found that the VEGF164/NRP1 guided migration of facial branchiomotor neurons was dependent on the presence of HSPGs. Taken together, these results provide evidence for the differential requirement of HSPGs in VEGF164-­‐driven neural, but not endothelial cell patterning in the hindbrain.

Type: Thesis (Doctoral)
Title: Molecular mechanisms controlling neurovascular patterning
Open access status: An open access version is available from UCL Discovery
Language: English
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology
URI: https://discovery.ucl.ac.uk/id/eprint/1317773
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