NogoB receptor is essential for extraembryonic vascular development and protein glycosylation

Abstract

Nogo‐B receptor (NgBR) was identified as an interacting protein necessary for NogoB stimulated chemotaxis and tube formation of endothelial cells in vitro. Recently, our lab has shown that NgBR interacts with dehydrodolichyl diphosphate synthase (DHDDS), enhances DHDDS protein stability, and promotes cis‐IPTase activity in vitro. To investigate NgBR function in vivo, we have generated conditional knockout mice. We have found that global deficiency of NgBR results in peri‐implantation embryonic lethality before e6.5. Furthermore, to specifically study the function of NgBR in the endothelial cells, we also generated NgBR cKO mice model using Tie2Cre. The NgBR cKO embryo died at E10.5 with vascular development defect in extraembryonic tissue. The yolk sac of the mutant embryo shows poorly organized and dilated primary capillaries. Moreover, most VEGFR2 in the mutant yolk sac was in the non‐glycosylated, non‐functional form rather than in the fully or semi‐glycosylated form of VEGFR2, which indicates that VEGFR2‐dependent signaling is down‐regulated in the mutant. The mutant also had decreased expression of endothelial cell markers. Taken together, these results suggest that during early embyronic development, NgBR has a role in extraembryonic vascular development by regulating protein N‐glycosylation. The NgBR cKO mice will provide a useful model system to investigate protein glycosylation in vivo.