The β8 integrin cytoplasmic domain activates extracellular matrix adhesion to promote brain neurovascular development

Abstract

In the developing mammalian brain neuroepithelial cells interact with blood vessels to regulate angiogenesis, blood-brain barrier (BBB) maturation, and other key neurovascular functions. Genetic studies in mice have shown that sprouting neurovascular development is controlled, in part, by Itgb8 which encodes the neuroepithelial cell-expressed integrin b8 subunit. However, these studies have involved complete loss-of-function Itgb8 mutations, and have not discerned the relative roles for the b8 integrin extracellular matrix (ECM) binding region versus the intracellular signaling tail. Here, Cre/lox strategies have been employed to selectively delete the cytoplasmic domain of Itgb8 without perturbing its transmembrane and extracellular domains. We report that the b8 integrin cytoplasmic domain is essential for inside-out modulation of adhesion, including activation of latent-TGFbs in the ECM. Quantitative sequencing of the brain endothelial cell transcriptome identifies TGFb-regulated genes with putative links to blood vessel morphogenesis, including several genes linked to Wnt/b-catenin signaling. These results reveal that the b8 integrin cytoplasmic domain is essential for the regulation of TGFb-dependent gene expression in endothelial cells and suggest that cross-talk between TGFbs and Wnt pathways is critical for neurovascular development.

Cerebral furin deficiency causes hydrocephalus in mice

“…As a member of the integrin family that plays an important role in brain assembly, 75 ITGB8 also regulates angiogenesis and embryo implantation. 76 , 77 In the radial glia, ITGB8 contributes to the expansion of the human brain during development 78 ; and the function of the decreased FGA is supported by that FGA-KO facilitates the growth and metastasis of lung cancer through integrin-AKT signaling. 79 It could be likely that these changes are associated with enhanced GFAP staining and astrocytic overgrowth ( Fig.…”

Urinary exosomal microRNAs as predictive biomarkers for persistent psychotic-like experiences

“…Additionally, experimental evidence for hsa-miR-142-3p, hsa-miR-199a-3p, and hsa-miR-486-5p in the regulation of ITGB8 is available [63][64][65] . ITGB8 is a member of the integrin beta chain family, which plays an important role in neurovascular development, synaptogenesis, synaptic stabilization, and maintenance by regulating ECM interaction [66][67][68] . These synaptic changes caused by ECM abnormalities are often observed in schizophrenia 44 .…”

A year in review: brain barriers and brain fluids research in 2022

“…Nirwane and Yao [ 40 ] have also recently reviewed the cell specific expression of different laminins within the NVU and their function. De et al [ 41 ] have found that β8-integrin activates extracellular matrix adhesion to promote cerebrovascular development. β8-integrin is essential for transforming growth factor β-dependent gene expression in the endothelium.…”