Medical College of Wisconsin
CTSICores SearchResearch InformaticsREDCap

Nogo-B receptor deficiency causes cerebral vasculature defects during embryonic development in mice. Dev Biol 2016 Feb 15;410(2):190-201

Date

01/10/2016

Pubmed ID

26746789

Pubmed Central ID

PMC4767500

DOI

10.1016/j.ydbio.2015.12.023

Scopus ID

2-s2.0-84957847497   13 Citations

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.

Author List

Rana U, Liu Z, Kumar SN, Zhao B, Hu W, Bordas M, Cossette S, Szabo S, Foeckler J, Weiler H, Chrzanowska-Wodnicka M, Holtz ML, Misra RP, Salato V, North PE, Ramchandran R, Miao QR

Authors

Magdalena Chrzanowska PhD Associate Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
Suresh Kumar PhD Associate Professor in the Pathology department at Medical College of Wisconsin
Ravindra P. Misra PhD Dean, Professor in the Biochemistry department at Medical College of Wisconsin
Paula E. North MD, PhD Professor in the Pathology department at Medical College of Wisconsin
Ramani Ramchandran PhD Professor in the Pediatrics department at Medical College of Wisconsin
Hartmut Weiler PhD Associate Professor in the Physiology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Blood Vessels
Cerebrovascular Circulation
Female
Mice
Mice, Knockout
Pregnancy
Receptors, Cell Surface
jenkins-FCD Prod-482 91ad8a360b6da540234915ea01ff80e38bfdb40a