Nogo-B receptor deficiency causes cerebral vasculature defects during embryonic development in mice

Abstract

Nogo-B receptor (NgBR) was identified as a receptor specific for Nogo-B. Our previous work has shown that Nogo-B and its receptor (NgBR) are essential for chemotaxis and morphogenesis of endothelial cells in vitro and intersomitic vessel formation via Akt pathway in zebrafish. Here, we further demonstrated the roles of NgBR in regulating vasculature development in mouse embryo and primitive blood vessel formation in embryoid body culture systems, respectively. Our results showed that NgBR homozygous knockout mice are embryonically lethal at E7.5 or earlier, and Tie2Cre-mediated endothelial cell-specific NgBR knockout (NgBR ecKO) mice die at E11.5 and have severe blood vessel assembly defects in embryo. In addition, mutant embryos exhibit dilation of cerebral blood vessel, resulting in thin-walled endothelial caverns. The similar vascular defects also were detected in Cdh5(PAC)-CreERT2 NgBR inducible ecKO mice. Murine NgBR gene-targeting embryonic stem cells (ESC) were generated by homologous recombination approaches. Homozygous knockout of NgBR in ESC results in cell apoptosis. Heterozygous knockout of NgBR does not affect ESC cell survival, but reduces the formation and branching of primitive blood vessels in embryoid body culture systems. Mechanistically, NgBR knockdown not only decreases both Nogo-B and VEGF-stimulated endothelial cell migration by abolishing Akt phosphorylation, but also decreases the expression of CCM1 and CCM2 proteins. Furthermore, we performed immunofluorescence (IF) staining of NgBR in human cerebral cavernous malformation patient tissue sections. The quantitative analysis results showed that NgBR expression levels in CD31 positive endothelial cells is significantly decreased in patient tissue sections. These results suggest that NgBR may be one of important genes coordinating the cerebral vasculature development.

Characterization of iPSCs derived from low grade gliomas revealed early regional chromosomal amplifications during gliomagenesis

“…Immunohistochemistry was performed as described [17]. In brief, paraffin sections were deparaffinized in xylene and rehydrated in decreasing concentration of ethanol solutions.…”

Nogo-B receptor increases the resistance to tamoxifen in estrogen receptor-positive breast cancer cells

“…NgBR was identified as a Nogo-B receptor specific for the amino terminus of Nogo-B (AmNogo-B). NgBR is necessary for angiogenesis by mediating chemotaxis of endothelial cells [ 12 ], and is essential for vasculature development [ 13 , 14 ]. Our recent findings demonstrated that NgBR binds farnesylated Ras and recruits Ras to the plasma membrane, which is a critical step required for receptor tyrosine kinase (RTK)-mediated activation of Ras signaling in human breast cancer cells and tumorigenesis [ 15 ].…”

Endothelial miR-26a regulates VEGF-Nogo-B receptor-mediated angiogenesis

“…Accumulating evidence indicates an important role for Nogo-B receptor (NgBR) signaling and the expression level of this receptor in angiogenesis ( 10 – 13 ). NgBR is a transmembrane receptor protein that has been identified as a Nogo-B-binding protein and is essential for the Nogo-B-mediated chemotaxis of ECs and their organization into tubes ( 10 ).…”