Understanding the function and signalling mechanisms of VEGF-A and VEGF-C in optic chiasm development.

During development, the billions of nerve cells in our brains and eyes must make appropriate connections with correct target regions. This is achieved by the directed guidance of neuronal processes along highly specific pathways, which are laid down by chemical cues. Mistakes made during axon pathfinding from the eye to the brain, for example as a result of loss of eye pigmentation in albinism, result in an impaired ability to see in depth. Moreover, defects in axon pathfinding within the brain have been linked to the development of disorders such as autism and schizophrenia. Understanding how brain and eye connections form normally may also help devise novel strategies for nerve regeneration following injury or damage to the adult nervous system, for example following optic nerve damage or stroke. Recently, we discovered that a molecule best characterised as a growth factor for blood vessels, which is known as vascular endothelial growth factor (VEGF-A), affects nerve wiring between the eye and brain. Specifically, we found that VEGF-A is essential for the routing of nerve processes that extend from each eye into the opposite brain hemisphere to help us see objects in depth. More recently, we discovered that a related molecule called VEGF-C also affects nerve wiring between the eye and brain. We now seek funding to determine the precise role of VEGF-C in this process, to investigate how VEGF-A and VEGF-C cooperate in establishing the wiring that is necessary for normal vision, and to establish how their signals are transmitted within the nerve cables. This research will advance our understanding of normal brain wiring and, in the future, will likely advance the development of clinical therapies that promote repair and regeneration following damage to the eye and its brain targets.

The segregation of retinal ganglion cell (RGC) axons at the optic chiasm into contralateral and ipsilateral projections is a process essential for stereovision and an excellent model system to investigate axon guidance decisions. We have demonstrated recently that the VEGF164 isoform of the classical angiogenic factor VEGF-A binds its receptor neuropilin 1 (NRP1) on RGC axons destined for the contralateral optic tract to help them cross the optic chiasm. Our pilot data suggest that a related molecule known best for its function in the lymphatic vasculature, VEGF-C, also directly regulates axon guidance at the chiasm midline. We now wish to extend these findings to identify the precise role of VEGF-C and its main receptor, VEGFR3 at the optic chiasm and to establish if co-operative interactions between VEGF-A and VEGF-C are important for establishing stereovision. We further wish to understand how NRP1 transmits the VEGF-A signals that control RGC axon guidance. We already know from our pilot experiments that NRP1 requires a co-receptor to transmit VEGF-A signals in RGCs and that this co-receptor is neither of the classical vascular VEGF-A receptors, VEGFR1 or VEGFR2. We will use a combination of expression, genetic, functional and biochemical assays to identify the NRP1 interacting protein(s) that convey VEGF-A signals in RGCs. The proposed programme of work will advance significantly our understanding of the mechanisms that establish stereovision and provide fundamental information on the role of classical vascular factors in neural circuit formation.

This project will significantly enhance our knowledge of the developmental processes that establish functional brain wiring patterns. Beyond their interest to the academic community, the results will impact on several other identifiable beneficiaries:

Commercial private sector: Because this work will identify novel functions and signalling pathways of VEGF family proteins in neurons, the results are likely to be of interest to the commercial sector involved in developing novel therapeutics for patients with neurodegenerative disorders or neurological injury, as they may be able to capitalise on this new knowledge. For example, companies marketing VEGF-A therapies for other purposes may consider that VEGF-A therapies have new applications in regenerative medicine, or identify VEGF-C as a new commercial target. Accordingly, this project is likely to contribute new knowledge that will lead to more translational research in the medium term, and may benefit regenerative and repair medicine to impact positively on public health in the UK and abroad in the long term. The fields of neurodegenerative disorders and neurological trauma in particular are areas of unmet clinical need with high social and economic importance.

Public: An immediate impact of this project is its opportunity to raise awareness and understanding of science and research through public dissemination of novel findings and explaining their significance. Knowledge of the developmental processes sculpting normal brain and eye development is key to understanding how we carry out everyday tasks, such as those that involve sight, sound, smell, learning and memory, etc. Studies of the mechanisms controlling axon growth and pathfinding will also improve the public's understanding of the origins of neurodevelopmental disorders that have been linked to deficits in brain wiring patterns. These topics will be incorporated in outreach activities to engage with the public about this work.

UK and International Research Base: By endowing researchers with both project specific and transferable skills, this project will lead to highly skilled workers that will benefit the UK's economic competitiveness. The project will also lead to new international collaborations and therefore enhance knowledge transfer and increase the international profile of our Universities.