GABAergic interneurons, born in remote germinative zones in the ventral forebrain (telencephalon) migrate tangentially into the cortex to adopt their specific positions. The cell types and molecular cues that regulate this migration remain to be elucidated. We have identified two populations of endothelial cells (pial and periventricular) in the embryonic telencephalon, each with distinct developmental patterns and transcription factor expression. While the pial vessels of the telencephalon are derivatives of the perineural plexuses surrounding the neural tube from the earliest stages of development, the periventricular vessel network develops in an orderly ventral to dorsal gradient, and enters the dorsal telecephalon a day prior to migration of GABAergic interneurons. Our preliminary studies show that the periventricular vessel network in the embryonic telencephalon is spatially and temporally well positioned to influence migration of GABAergic interneurons from the basal to the dorsal telencephalon. This application will examine whether the pial and periventricular vessel networks independently regulate migration and sorting of GABAergic interneurons to specific cortical regions. GABAergic interneurons form two spatially distinct streams in the dorsal cerebral wall, one that is immediately adjacent to the pial network and the second that is enwrapped by the periventricular network.
In specific aim 1, we will examine if the periventricular vessel network provides a scaffold for migration of the interneurons by time-lapse imaging, whole mounts and immunohistochemistry techniques.
In specific aims 2 A and 2B, we will test if either the pial endothelial cells or periventricular endothelial cells provide distinct guidance cues in the migration of GABAergic interneurons by in vitro transplantation and cell migration assays. In addition, in specific aim 2C, gene expression profiles of pial endothelial cells, periventricular endothelial cells and cortical GABAergic interneurons will be analyzed by microarrays to identify novel cross-talks between these cell types. Results could have far-reaching effects on concepts and mechanisms of regulation of angiogenesis and neuronal migration throughout the developing CNS.
The studies proposed here will offer novel insights into the molecular control of neural migration and will have implications for understanding malformations of cortical development (MCD) which is the morphological and physiological basis of several neurological diseases.
|Won, Chungkil; Lin, Zhicheng; Kumar T, Peeyush et al. (2013) Autonomous vascular networks synchronize GABA neuron migration in the embryonic forebrain. Nat Commun 4:2149|
|Li, Suyan; Haigh, Katharina; Haigh, Jody J et al. (2013) Endothelial VEGF sculpts cortical cytoarchitecture. J Neurosci 33:14809-15|
|Vasudevan, Anju; Won, Chungkil; Li, Suyan et al. (2012) Dopaminergic neurons modulate GABA neuron migration in the embryonic midbrain. Development 139:3136-41|