Tillo, M; (2015) Defining novel molecular mechanisms in hindbrain development. Doctoral thesis , (UCL) University College London.

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Abstract

During development, neurons migrate to their correct position and extend axons to their appropriate targets to form functional neuronal networks. Both these processes require the combination of many molecular signals. The hindbrain is a powerful model to uncover specific roles of these signals in axon guidance and neuronal migration. I have used the hindbrain model to investigate roles for specific isoforms of the vascular endothelial growth factor (VEGF-A) and enzymes that modify heparan sulfate proteoglycans (HSPGs) in motor neuron migration and cranial nerve development. VEGF-A is a potent angiogenic signal that has been described to also have functions during nervous system development. VEGFA is an alternatively spliced gene and its three main isoforms are termed VEGF121, VEGF165 and VEGF189. VEGF165 can bind the transmembrane receptor neuropilin 1 (NRP1) to regulate axon guidance, neuronal migration and neuronal survival, whilst VEGF121 is unable to signal through NRP1. Using in situ ligand-binding assays, I show that VEGF189 can also bind NRP1 in vivo, similar to VEGF165 and unlike VEGF121. Furthermore, I show that VEGF189 can promote NRP1-dependent migration of facial branchiomotor (FBM) neurons similar to VEGF165, and also has similar functions in retinal ganglion cell guidance at the optic chiasm and neuronal survival in the nose. HSPGs are extracellular matrix proteins that interact with various signalling proteins, including VEGF-A, but also fibroblast growth factors (FGFs) and their receptors. I found that the HSPG modifying enzymes HS6ST1 and HS6ST2 cooperate during cranial axon guidance, while HS2ST is required for normal FBM neuron migration. Furthermore, I demonstrated that HS2ST is dispensable for VEGF/NRP1-dependent FBM neuron migration, but promotes a novel pathway involving FGF-induced migration of these neurons. Finally, I investigated the suitability of genetic tools to study FBM neuron migration and cranial axon guidance.

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