Anju Vasudevan - US grants

DESCRIPTION (provided by applicant): 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 2A 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. PUBLIC HEALTH RELEVANCE: 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.

DESCRIPTION (provided by applicant): The central nervous system (CNS) acquires its vasculature by angiogenesis, a process consisting of proliferation of endothelial cells in existing blood vessels or vascular plexuses, and leading to the formation of new blood vessels. Notions of cerebral vascularization often depict CNS angiogenesis as a passive process driven primarily by demands of oxygen and to meet the metabolic needs of growing neuronal populations. They treat the developing endothelial network as a homogenous population. Our work has challenged these notions and shown that telencephalic blood vessels fall into two categories: pial and periventricular, based on anatomical location, independent growth patterns and developmental regulation. The neural tube acting as a vessel patterning nexus, directs the formation of the pial vessels that encompass it. The pial vessels do not display developmental gradients and are present circumscribing the entire telencephalon by embryonic day 9 (E9). The periventricular vessels on the other hand are branches of a basal vessel located in the basal ganglia primordium that likely arises from the pharyngeal arch arteries in the cervical region by E9. The periventricular vessel network propagates in an orderly lattice pattern into the dorsal telencephalon by E11 regulated by homeobox transcription factors. This application will test the central hypothesis that periventricular endothelial cells provide critical cues for the establishment of later forming neuronal gradients in the embryonic telencephalon. It aims at highlighting the autonomy of periventricular endothelial cell development and how it is regulated independently of neuronal development. It explores the novel concept that periventricular endothelial cells have an agenda of their own with remarkable versatility in being able to sculpt neuronal networks. It attempts to tap into the tremendous potential of periventricular endothelial cells as a therapeutic source for recovery of neurological function in many diverse scenarios. Results will have far-reaching effects on concepts and mechanisms of regulation of angiogenesis, offer new perspectives on telencephalic histogenesis principles and will lead to discoveries with unprecedented implication for treatment of many neurological disorders.

Abstract The cerebral cortex is essential for integration and processing of information that is required for most behaviors. Correct functioning of the cerebral cortex necessitates the concerted assembly of circuits involving glutamatergic projection neurons and GABAergic interneurons. The exquisitely precise laminar arrangement of neurons, axon collaterals and dendritic processes arises during embryonic development when neurons migrate successively from proliferative ventricular zones to coalesce into specific cortical layers. While radial glia was identified as substrates or guide rails for migration of projection neuron precursors to the cortical plate in the early seventies, the substrate for GABAergic interneuron migration was a missing link. Our recent work has shown that pre-formed vascular networks in the embryonic forebrain are strategically positioned to fulfill the formidable task of providing support and guidance cues to GABA neurons as they migrate from the subpallium to the developing cerebral cortex. This application will examine this novel paradigm of endothelial cell-neuron interactions at detailed cellular and molecular levels. It will elucidate the importance of new signaling mechanisms via forebrain endothelial cells that were hitherto believed to be exclusively neuronal. It will examine how alterations in these novel developmental pathways disturb hierarchical vascular patterns; perturb neuronal migration and cortical organization. Results will illustrate a powerful impact on cerebral cortex circuitry, blood flow and postnatal behavior with new significance for psychiatric disorders.

Abstract The central nervous system (CNS) acquires its vasculature by angiogenesis, a process that is critical for its development and repair. Our work has changed notions of cerebral vascularization which implied that blood vessels sprout passively into the brain parenchyma from pial vascular plexuses to meet metabolic needs of growing neuronal populations or treated endothelial cells of the CNS as a homogenous population. Based on origins, anatomical location, independent growth patterns and developmental regulation, forebrain vascular networks fall into two categories: pial and periventricular. The periventricular vascular network that develops in advance of and independent of neuronal development is strategically positioned to provide support and critical guidance cues to instruct neurogenesis and GABAergic interneuron migration in the developing telencephalon. These findings offer new solutions for transplanted primary neuronal precursors that are unable to migrate and integrate into regions requiring new neurons in the absence of proper guidance mechanisms. This application will explore this novel paradigm of neurovascular interactions in diverse ways. It will identify novel angiogenesis mechanisms underlying the origin and etiology of neuropsychiatric diseases. It aims to highlight the novel concept that endothelial GABA signaling is indispensable for brain development shaping postnatal and adult behavior. It attempts to rescue abnormal vascular GABA signaling during embryonic development as a therapeutic approach for long-lasting mental health outcomes. It will examine whether periventricular?like human endothelial cells promote human GABAergic neuronal migration to facilitate development of novel cell based therapies for GABA-related diseases. Results will have far-reaching effects on concepts and mechanisms of regulation of angiogenesis, offer new perspectives on telencephalic histogenesis principles and will lead to discoveries with unprecedented implications for regenerative medicine and treatment of many neurological and psychiatric diseases.