Abstract
Here we investigate the role of hypoxia inducible factor (HIF)-2α in coordinating the development of retinal astrocytic and vascular networks. Three Cre mouse lines were used to disrupt floxed Hif-2α, including Rosa26CreERT2, Tie2Cre, and GFAPCre. Global Hif-2α disruption by Rosa26CreERT2 led to reduced astrocytic and vascular development in neonatal retinas, whereas endothelial disruption by Tie2Cre had no apparent effects. Hif-2α deletion in astrocyte progenitors by GFAPCre significantly interfered with the development of astrocytic networks, which failed to reach the retinal periphery and were incapable of supporting vascular development. Perplexingly, the abundance of strongly GFAP+ mature astrocytes transiently increased at P0 before they began to lag behind the normal controls by P3. Pax2+ and PDGFRα+ astrocytic progenitors and immature astrocytes were dramatically diminished at all stages examined. Despite decreased number of astrocyte progenitors, their proliferation index or apoptosis was not altered. The above data can be reconciled by proposing that HIF-2α is required for maintaining the supply of astrocyte progenitors by slowing down their differentiation into non-proliferative mature astrocytes. HIF-2α deficiency in astrocyte progenitors may accelerate their differentiation into astrocytes, a change which greatly interferes with the replenishment of astrocyte progenitors due to insufficient time for proliferation. Rapidly declining progenitor supply may lead to premature cessation of astrocyte development. Given that HIF-2α protein undergoes oxygen dependent degradation, an interesting possibility is that retinal blood vessels may regulate astrocyte differentiation through their oxygen delivery function. While our findings support the consensus that retinal astrocytic template guides vascular development, they also raise the possibility that astrocytic and vascular networks may mutually regulate each other's development, mediated at least in part by HIF-2α.
Highlights
Retinal vascular development is closely associated with the development of an astrocytic template
Because HIF2a protein undergoes oxygen dependent degradation, our findings suggest that retinal vascular development may modulate astrocyte development by regulating Hif-2a protein levels
Two GFAPCre lines were purchased from the Jackson laboratory, including a line originally generated by Albee Messing (Jax stock number 004600) [23] and another line donated by Michael Sofroniew [24]
Summary
Retinal vascular development is closely associated with the development of an astrocytic template. Earlier studies found that retinal astrocytes were present in animal species with vascularized retinas but absent in animals with avascular retinas [1]. More recent studies employed gene targeting approach in mice to address the relationship between astrocytic and vascular development. Tlx null mice displayed poor assembly of extracellular fibronectin matrices [3], and astrocyte specific Tlx disruption further demonstrated that the expression of both fibronectin and heparan-sulfate was compromised [4]. These extracellular components were thought to mediate retinal vascularization by regulating VEGF-A binding and distribution [4]
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