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Veins have emerged as the origin of all other endothelial cell subtypes needed to expand vascular networks during developmental and pathological neoangiogenesis. Here, we uncover the role of the angioneurin Fibronectin Leucine Rich Transmembrane protein (FLRT) 2 in central nervous system (CNS) vascular development in the mouse. Early postnatal FLRT2 deletion reveals specific defects in retinal veins, impacting endothelial cell proliferation, sprouting and polarity that result in reduced tip cells at the vascular front. FLRT2 interacts with VE-cadherin and together with the endocytic adaptor protein Numb contribute to the modulation of adherens junction morphology in both retina and cerebral cortex in vivo. Utilizing expansion microscopy, we visualize the altered dynamic distribution of VE-cadherin in tissue of FLRT2 endothelial mutants. Additionally, FLRT2 in cortical vessels regulates the crosstalk between adherens and tight junctions, influencing blood-brain barrier development. Our findings position FLRT2 as a vein-specific regulator of CNS vascular development., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Neuron migration is a hallmark of nervous system development that allows gathering of neurons from different origins for assembling of functional neuronal circuits. Cortical inhibitory interneurons arise in the ventral telencephalon and migrate tangentially forming three transient migratory streams in the cortex before reaching the final laminar destination. Although migration defects lead to the disruption of inhibitory circuits and are linked to aspects of psychiatric disorders such as autism and schizophrenia, the molecular mechanisms controlling cortical interneuron development and final layer positioning are incompletely understood. Here, we show that mouse embryos with a double deletion of FLRT2 and FLRT3 genes encoding cell adhesion molecules exhibit an abnormal distribution of interneurons within the streams during development, which in turn, affect the layering of somatostatin+ interneurons postnatally. Mechanistically, FLRT2 and FLRT3 proteins act in a noncell-autonomous manner, possibly through a repulsive mechanism. In support of such a conclusion, double knockouts deficient in the repulsive receptors for FLRTs, Unc5B and Unc5D, also display interneuron defects during development, similar to the FLRT2 / FLRT3 mutants. Moreover, FLRT proteins are chemorepellent ligands for developing interneurons in vitro , an effect that is in part dependent on FLRT-Unc5 interaction. Together, we propose that FLRTs act through Unc5 receptors to control cortical interneuron distribution in a mechanism that involves cell repulsion. SIGNIFICANCE STATEMENT Disruption of inhibitory cortical circuits is responsible for some aspects of psychiatric disorders such as schizophrenia or autism. These defects include interneuron migration during development. A crucial step during this process is the formation of three transient migratory streams within the developing cortex that determine the timing of interneuron final positioning and the formation of functional cortical circuits in the adult. We report that FLRT proteins are required for the proper distribution of interneurons within the cortical migratory streams and for the final laminar allocation in the postnatal cortex. These results expand the multifunctional role of FLRTs during nervous system development in addition to the role of FLRTs in axon guidance and the migration of excitatory cortical neurons., (Copyright © 2021 the authors.)

Purpose of the Review: The synchronic development of vascular and nervous systems is orchestrated by common molecules that regulate the communication between both systems. The identification of these common guiding cues and the developmental processes regulated by neurovascular communication are slowly emerging. In this review, we describe the molecules modulating the neurovascular development and their impact in processes such as angiogenesis, neurogenesis, neuronal migration, and brain homeostasis., Recent Findings: Blood vessels not only are involved in nutrient and oxygen supply of the central nervous system (CNS) but also exert instrumental functions controlling developmental neurogenesis, CNS cytoarchitecture, and neuronal plasticity. Conversely, neurons modulate CNS vascularization and brain endothelial properties such as blood-brain barrier and vascular hyperemia., Summary: The integration of the active role of endothelial cells in the development and maintenance of neuronal function is important to obtain a more holistic view of the CNS complexity and also to understand how the vasculature is involved in neuropathological conditions., Competing Interests: Conflict of interest statement Nothing declared., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)