Norrin stimulates cell proliferation in the superficial retinal vascular plexus and is pivotal for the recruitment of mural cells

作者：Zuercher Jurian; Fritzsche Martin; Feil Silke; Mohn Lucas; Berger Wolfgang^*

来源：Human Molecular Genetics, 2012, 21(12): 2619-2630.

DOI：10.1093/hmg/dds087

Mutations in Norrin, the ligand of a receptor complex consisting of FZD4, LRP5 and TSPAN12, cause severe developmental blood vessel defects in the retina and progressive loss of the vascular system in the inner ear, which lead to congenital blindness and progressive hearing loss, respectively. We now examined molecular pathways involved in developmental retinal angiogenesis in a mouse model for Norrie disease. Comparison of morphometric parameters of the superficial retinal vascular plexus (SRVP), including the number of filopodia, vascular density and number of branch points together with inhibition of Notch signaling by using DAPT, suggest no direct link between Norrin and Notch signaling during formation of the SRVP. We noticed extensive vessel crossing within the SRVP, which might be a loss of Wnt- and MAP kinase-characteristic feature. In addition, endomucin was identified as a marker for central filopodia, which were aligned in a thorn-like fashion at P9 in Norrin knockout (Ndp(y/)) mice. We also observed elevated mural cell coverage in the SRVP of Ndp(y/) mice and explain it by an altered expression of PDGF and its receptor (PDGFR). In vivo cell proliferation assays revealed a reduced proliferation rate of isolectin B4-positive cells in the SRVP from Ndp(y/) mice at postnatal day 6 and a decreased mitogenic activity of mutant compared with the wild-type Norrin. Our results suggest that the delayed outgrowth of the SRVP and decreased angiogenic sprouting in Ndp(y/) mice are direct effects of the reduced proliferation of endothelial cells from the SRVP.

• 出版日期2012-6-15
• 单位河北医科大学