Directed migration of retinal astrocytes by PDGF signaling

Abstract

PurposeProper patterning of astrocytes is crucial for retinal angiogenesis in both rodents and human. Platelet‐derived growth factor (PDGF) is one of the key regulators of cell migration, but distinctive downstream pathways have been implicated in a variety of cell types. Herein we investigated the detailed mechanism of PDGFA‐directed astrocyte migration in early postnatal mouse retina.MethodsTransgenic mice with glia‐specific deletion of PDGFRα and multiple potential downstream effectors of PDGF signaling pathway are generated. Perinatal astrocytes and retinal vasculature are evaluated by whole mount IHC.ResultsAstrocyte migration and retinal angiogenesis are severely impaired in knockout mice of PDGFRα. This is phenocopied by mutations in PI3K catalytic subunits p110αβ, as well as in mutations of PI3K binding site in PDGFRα. Rac/Rap mediated cytoskeleton rearrangement is also imperative for the patterning of astrocytic network. On the other hand, disruption of mTOR signaling by knocking out binding partner Raptor or Rictor had no effect on astrocyte motility. PLCγ pathway, which is essential for PDGF chemotaxis in mesenchymal cells, is also dispensable for astrocyte migration.ConclusionsThis study demonstrated that PDGFA‐directed astrocyte migration is mediated through PI3K and Rac/Rap signaling, but not PLCγ or Akt/mTOR pathway. These findings add mechanistic insight into cell type‐specific regulation of migration by PDGF.