Defining the role of VEGF-A signalling in glia during development and in regeneration

Glial cells nourish and support the information-transmitting neuronal cells of the central nervous system (brain and spinal cord) and the peripheral nervous system (ganglia and nerves). Whilst healthy glia promotes neuronal function, unhealthy glia causes diseases such as multiple sclerosis, diabetic neuropathy and Charcot-Marie-Tooth-Disease. Our pilot experiments suggest that the protein Vascular Endothelial Growth Factor (VEGF) is important for two glial cell types named boundary cap cells and Schwann cells. Boundary caps cells help nerve fibres to cross between the central and peripheral nervous system during development, if therapies were identified that could regenerate boundary caps from their stem cell-like precursors, we could help nerve fibres that re-grow in adults after injury to extend back into the central nervous system. Schwann cells form wrap myelin sheets around nerve fibres to insulate them against each other electrically, and they also help nerve fibres re-grow after injury. Importantly, new Schwann cells can also be generated from boundary cap precursors. We want to find out how VEGF instructs boundary cap and Schwann cells to grow and position themselves in appropriate places during development and disease, in order to identify new molecular targets for medical therapies that promote nerve repair and halt neurodegeneration.

Glial cells nourish and support the neurons of the central and peripheral nervous systems. Whilst healthy glia promotes neuronal function, glial cell dysfunction contributes to neurodegeneration. Accordingly, the study of glial cell development, growth and survival is of enormous clinical significance. The trophic role of growth factors in promoting the proliferation and survival of glia has been studied extensively, but much less is known about the molecules that guide glial cells from their birthplace to their axonal targets. Moreover, the mechanisms that integrate glial cells with neurons and vessels are still unknown, even though the disruption of their interaction in diseases and their reassembly during medical treatment present important clinical issues. Recent work in culture models suggests that the secreted glycoprotein Vascular Endothelial Growth Factor (VEGF-A) supports glial and axonal growth in addition to its well-known functions in blood vessels. However, it remains unclear whether VEGF-A directly affects glial cell behaviour in vivo, or if VEGF-stimulated vessel and axon growth indirectly contribute to enhanced glia production and survival. Moreover, it is not known whether there is a difference between glial, vascular and neuronal growth with respect to VEGF-A isoform signaling. Our pilot studies of nerve development in mice with precisely engineered mutations indicate that specific VEGF-A isoforms control the behaviour of two neural crest-derived glial cell populations, boundary cap cells and Schwann cells. We now wish to dissect the precise roles of VEGF-A signaling in the growth, differentiation and survival of these glial cell types, with the aim to identify molecular pathways that may be targeted in concert with blood vessels to promote nerve repair and halt neurodegeneration.