title: 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.
authors.affiliation: Division of Pediatric Surgery, Department of Surgery, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Division of Pediatric Pathology, Department of Pathology, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Children's Research Institute, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
authors.forename: Ujala
authors.initials: U
authors.lastname: Rana
authors.affiliation: Division of Pediatric Surgery, Department of Surgery, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Division of Pediatric Pathology, Department of Pathology, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Children's Research Institute, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Division of Pediatric Pathology, Department of Pathology, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Children's Research Institute, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
authors.forename: Suresh N
authors.initials: SN
authors.lastname: Kumar
authors.affiliation: Division of Pediatric Surgery, Department of Surgery, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Division of Pediatric Pathology, Department of Pathology, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Children's Research Institute, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
authors.forename: Baofeng
authors.initials: B
authors.lastname: Zhao
authors.affiliation: Division of Pediatric Surgery, Department of Surgery, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Division of Pediatric Pathology, Department of Pathology, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Children's Research Institute, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
authors.forename: Wenquan
authors.initials: W
authors.lastname: Hu
authors.affiliation: Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Children's Research Institute, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Bordas
authors.affiliation: Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Children's Research Institute, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Cossette
authors.affiliation: Division of Pediatric Pathology, Department of Pathology, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Children's Research Institute, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Szabo
authors.affiliation: Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA; BloodCenter of Wisconsin, Milwaukee, WI 53226, USA.
authors.forename: Jamie
authors.initials: J
authors.lastname: Foeckler
authors.affiliation: Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA; BloodCenter of Wisconsin, Milwaukee, WI 53226, USA.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Weiler
authors.affiliation: BloodCenter of Wisconsin, Milwaukee, WI 53226, USA.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Chrzanowska-Wodnicka
authors.affiliation: Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
authors.forename: Mary L
authors.initials: ML
authors.lastname: Holtz
authors.affiliation: Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
authors.forename: Ravindra P
authors.initials: RP
authors.lastname: Misra
authors.affiliation: Division of Pediatric Pathology, Department of Pathology, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Children's Research Institute, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
authors.forename: Valerie
authors.initials: V
authors.lastname: Salato
authors.affiliation: Division of Pediatric Pathology, Department of Pathology, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Children's Research Institute, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
authors.forename: Paula E
authors.initials: PE
authors.lastname: North
authors.affiliation: Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Children's Research Institute, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, WI 53226, USA. Electronic address: rramchan@mcw.edu.
authors.forename: Ramani
authors.initials: R
authors.lastname: Ramchandran
authors.affiliation: Division of Pediatric Surgery, Department of Surgery, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Division of Pediatric Pathology, Department of Pathology, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Children's Research Institute, Medical College of Wisconsin, Milwaukee, WI 53226, USA. Electronic address: qmiao@mcw.edu.
authors.forename: Qing Robert
authors.initials: QR
authors.lastname: Miao
mesh_terms: D000818:Animals; D001808:Blood Vessels / Q000196:embryology*; D002560:Cerebrovascular Circulation; D005260:Female; D051379:Mice; D018345:Mice, Knockout; D011247:Pregnancy; D011956:Receptors, Cell Surface / Q000235:genetics*
chemical_list: C512615:Nogo-B receptor, mouse; D011956:Receptors, Cell Surface