Tailless and hypoxia inducible factor-2 alpha cooperate to sustain proangiogenic states of retinal astrocytes in neonatal mice

Tailless (TLX, an orphan nuclear receptor) and hypoxia inducible factor-2 alpha (HIF2 alpha) are both essential for retinal astrocyte and vascular development. Tlx-/- mutation and astrocyte specific Hif2 alpha disruption in Hif2 alpha f/f/GFAPCre mice are known to cause defective astrocyte development and block vascular development in neonatal retinas. Here we report that TLX and HIF2 alpha support retinal angiogenesis by cooperatively maintaining retinal astrocytes in their proangiogenic states. While Tlx+/- and Hif2 alpha f/+/GFAPCre mice are phenotypically normal, Tlx+/-/Hif2 alpha f/+/GFAPCre mice display precocious retinal astrocyte differentiation towards non-angiogenic states, along with significantly reduced retinal angiogenesis. In wild-type mice, TLX and HIF2 alpha coexist in the same protein complex, suggesting a cooperative function under physiological conditions. Furthermore, astrocyte specific disruption of Phd2 (prolyl hydroxylase domain protein 2), a manipulation previously shown to cause HIF2 alpha accumulation, did not rescue retinal angiogenesis in Tlx-/- background, which suggests functional dependence of HIF2 alpha on TLX. Finally, the expression of fibronectin and VEGF-A is significantly reduced in retinal astrocytes of neonatal Tlx+/-/Hif2 alpha f/+/GFAPCre mice. Overall, these data indicate that TLX and HIF2 alpha cooperatively support retinal angiogenesis by maintaining angiogenic potential of retinal astrocytes.