Hypoxia inducible factor-2α regulates the development of retinal astrocytic network by maintaining adequate supply of astrocyte progenitors.
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 Rosa26(CreERT2), Tie2(Cre), and GFAP(Cre). Global Hif-2α disruption by Rosa26(CreERT2) led to reduced astrocytic and vascular development in neonatal retinas, whereas endothelial disruption by Tie2(Cre) had no apparent effects. Hif-2α deletion in astrocyte progenitors by GFAP(Cre) 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.
The Center for Vascular Biology, Department of Cell Biology, University of Connecticut Health Center, Farmington, Connecticut, United States of America.
Li-Juan
LJ
Duan
The Center for Vascular Biology, Department of Cell Biology, University of Connecticut Health Center, Farmington, Connecticut, United States of America.
Kotaro
K
Takeda
The Center for Vascular Biology, Department of Cell Biology, University of Connecticut Health Center, Farmington, Connecticut, United States of America.
Guo-Hua
GH
Fong
D000818:Animals; D001253:Astrocytes / Q000166:cytology* / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins / Q000172:deficiency / Q000378:metabolism*; D015153:Blotting, Western; D002454:Cell Differentiation / Q000502:physiology; D017931:DNA Primers / Q000235:genetics; D005455:Fluorescent Antibody Technique; D005838:Genotype; D051379:Mice; D008810:Mice, Inbred C57BL; D012160:Retina / Q000166:cytology* / Q000196:embryology* / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism / Q000502:physiology*; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D017931:DNA Primers; D000099162:Endothelial PAS Domain-Containing Protein 1