<p>(A) Outline of Snail stabilization by ECM-mediated signaling. Snail is rapidly degraded by the GSK3β-dependent proteosomal system. On exposure of ECs to ECM, they activate Akt, which can suppress GSK3β-dependent system by phosphorylating GSK3β (pGSK3β). This process stabilizes Snail by releasing it from GSK3β system. Thereby, the formation of Snail-Egr-1 complex promotes VEGFR3 expression by binding to the <i>VEGFR3</i> promoter region to facilitate EC morphogenesis, such as EC sprouting, extension, and branching. pSnail, phosphorylated Snail by GSK3β; pAkt, Akt phosphorylation; E, Egr-1; EC, endothelial cell. (B) Capillary branching morphogenesis is controlled by Snail. In P7–P8 mice, venous ECs in the superficial plexus start to extend capillary branching toward the deep retina in response to tissue needs. The sprouting ECs at the border between the GCL and IPL are exposed to ECM, which subsequently contributes to Snail induction and stabilization, followed by enhanced VEGFR3 expression. Snail/VEGFR3-expressing ECs vertically migrate toward deep retina. At P9–P11 mice, vertically migrating ECs reach in the boundary of INL and turn sideways to form the deep capillary plexus in the OPL region. Snail knockdown attenuates the initiation of EC sprouting, which subsequently impairs the formation of the deep capillary plexus.</p
