Editors' ChoiceDevelopmental Biology

Guiding vessels in the developing brain

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Sci. Signal.  22 Dec 2015:
Vol. 8, Issue 408, pp. ec378
DOI: 10.1126/scisignal.aaf1137

Similar to neuronal development, growing blood vessels in the developing brain need guidance. Neuroepithelial cells guide the developing blood vessels in the brain. The integrin αvβ8 on neuroepithelial cells binds latent transforming growth factor–β (TGF-β) complex in the extracellular matrix, stimulating the release of TGF-β, which signals the endothelial cells. Neuropilin 1 (Nrp1) is a receptor present on the endothelial cells and participates in angiogenesis in the developing brain through an unknown process that does not involve its well-established ligands (VEGF-A and semaphorins). Hirota et al. analyzed angiogenesis in the developing brains of mice and zebrafish to understand how Nrp1 functioned in this process. Mice with a vascular endothelial cell–specific knockout, engineered such that the mice survived to embryonic day 15 to enable analysis of the developing brain vasculature (hereafter referred to as Nrp1-knockout), showed focal regions of brain hemorrhage that were associated with aberrant patterning of the blood vessels. This phenotype is similar to that observed with mice globally or neuroepithelial cell–specifically lacking the β8 integrin subunit. Whereas control mice showed close juxtaposition of the blood vessels with neuroepithelial cells with colocalization of Nrp1 (endothelial cells) and αvβ8 integrin (neuroepithelial cells), the vessels and neuroepithelial cells were not closely associated in the Nrp1-knockout (endothelial cell–specific) or β8-knockout (global) mice. Nrp1 and the β8 integrin subunit coimmunoprecipitated from control mouse brains, suggesting that Nrp1 and αvβ8 (β8 only dimerizes with αv) interact, and experiments with transfected cells in culture indicated that the Nrp1 and β8 interacted in trans (across cells). Whereas the global β8-knockout mice had reduced phosphorylation of Smads, mediators of TGF-β signaling, the Nrp1-knockout mice had increased Smad phosphorylation, indicating that integrin signaling promoted TGF-β signaling and Nrp1 suppressed it. The endothelial tip cells, which are the ones at the front of the growing blood vessel, exhibited defective polarity in the Nrp1-knockout mice, and knockdown of Nrp1 in cultured endothelial cells resulted in disrupted focal adhesion formation, altered cytoskeletal dynamics, and defects in cell spreading and formation of lamellipodia. Thus, interactions between endothelial cells and neuroepithelial cells through Nrp1, αvβ8, and TGF-β are necessary for proper blood vessel formation in the developing brain.

S. Hirota, T. P. Clements, L. K. Tang, J. E. Morales, H. S. Lee, S. P. Oh, G. M. Rivera, D. S. Wagner, J. H. McCarty, Neuropilin 1 balances β8 integrin-activated TGFβ signaling to control sprouting angiogenesis in the brain. Development 142, 4363–4373 (2015). [PubMed]