Defining common molecular pathways in cortical interneuron migration and vascular development

In man, the cerebral cortex is by far the most important part of the brain containing the majority of its neurons. In mammals, neurons are divided into two broad classes, the excitatory pyramidal neurons that project to areas outside the cortex, and the nonpyramidal cells, the GABA-containing cortical interneurons. These cell types are generated in different germinal zones and follow distinct modes of migration to reach their final positions in the cortex: radial and tangential. All pyramidal neurons are generated in the ventricular zone of the embryonic cortex and migrate radially (i.e. perpendicular to the surface of the brain) using the support of glial fibres (gliophilic migration). Interneurons arise in the ganglionic eminence, an area in the basal telencephalon that gives rise to the basal ganglia. These cells follow long and tortuous routes to actively migrate into the developing cortex. Once in the cortex, they follow one of two main tangential (i.e. parallel to the pial surface) migratory streams before they turn radially to reach their positions in the developing cortical plate. It is thought that these cells use corticofugal axons to navigate from the basal telencephalon to the cortex (neurophilic migration) and radial glia in their final part of their journey within the cortical plate (gliophilic migration). However, evidence has recently emerged to support vasophilic mode of migration, where interneurons use the developing vascular network as a substrate for their movement. Here, we propose to test the hypothesis that various chemotropic factors, secreted by the vasculature, regulate the development and migration of interneurons. Specifically, we propose to combine mouse genetic tools with cell and molecular biological techniques to investigate the roles of blood vessel secreted molecules on the generation, survival and migration of cortical interneurons. We shall focus on vascular endothelial growth factor (VEGF), paying particular attention to the molecular mechanisms through which this angiogenic factor exerts its function in these developmental events. In addition to studying the role of VEGF in cortical interneuron migration, we wish to assess whether this and other blood vessel secreted factors dictate the choice of migratory stream by cortical interneurons. The proposed research programme will explore novel mechanisms in tangential neuronal migration, and enhance our understanding of the aetiologies of developmental disorders of this area of the brain such as mental retardation, autism and certain forms of epilepsy.

The mammalian cerebral cortex contains two broad classes of neurons: the excitatory (glutamatergic) pyramidal neurons and the inhibitory (GABAergic) interneurons. Pyramidal cells originate from the neuroepithelium of the cortical ventricular zone, whereas the interneurons arise from the ventral telencephalon. We have, in the past, studied the origin of interneurons and described their tortuous migratory routes into the developing cortex. We have also characterised some of the molecular mechanisms that regulate their migration. Recent studies have documented the close physical association between the vascular network in the developing forebrain and migrating interneurons, prompting speculation that these cells are guided by blood vessel secreted factors. Here, we propose to use a variety of in vivo and in vitro methods to test the hypothesis that secreted angiogenic factors in the developing forebrain, especially vascular endothelial growth factor (VEGF), play important roles in the generation, survival and migration of cortical interneurons. Once the function(s) of this factor is established, we propose to use mouse genetic models with molecular biological methods to identify the underlying signalling pathways. Further, we intend to address the question of whether this and other angiogenic factors mediate the choice of migratory stream by cortical interneurons. Studies of the molecular mechanisms involved in this novel vasophilic mode of interneuron migration will enhance our understanding of normal cortical development and of developmental disorders that affect the human brain.

Firstly, success of this application will have a huge impact on the life of our laboratory, as our current funding ends next year. Professor Parnavelas first established his laboratory, dedicated to working primarily in the field of cortical development, upon returning to the UK from the United States to take up a lectureship at UCL in 1983. Since then, he has remained in the same department and built a productive laboratory that remained in the forefront of the field. He has been successful in obtaining continuous grant support over the years and in providing a fertile ground for training of students, postdoctoral fellows and visiting scientists from around the world. Most of them have since gone to become independent and productive scientists. This grant, if successful, will allow us to investigate the novel question of vasophilic interneuron migration, and continue the tradition of training young scientists. The wide range of techniques included in this project, comprise highly transferable skills for people in the laboratory to use in other projects here or in other laboratories in the future.

The proposed programme of research aims to investigate the role of secreted molecules by blood vessels in the migration of cortical interneurons, focusing on the underlying mechanisms that support this process. This line of work complements our present and past interests, and those of other groups worldwide, on the molecular mechanisms involved in cortical interneuron migration. It will contribute to the existing body of knowledge about the genes and signalling pathways involved in this developmental process, and will undoubtedly benefit the work of basic scientists and clinicians alike, who are investigating the development and function of these cells in the normal brain and in disease. Indeed, interest in cortical neuron migration, especially for interneurons, has never been greater because a number of brain malformations in humans have recently been linked to their abnormal migration. Such defects include mental retardation, epilepsy, schizophrenia and autism. The identification of genes linked to these disorders is of paramount importance and may contribute to therapeutic approaches for these disorders. To highlight the impact of our research, we have recently defined the role of a chemorepulsive molecule (Semaphorin 3A) in the migration of another group of neurons, the neuroendocrine GnRH cells, which has subsequently been shown to be mutated in patients displaying symptoms related to abnormal migration of these cells.