Vhl safeguards thymic epithelial cell identity and thymopoietic capacity by constraining Hif1a activity during development.

The thymus is a physiologically hypoxic organ and fulfills its role of generating T cells under low-oxygen conditions. We have therefore investigated how thymic epithelial cells (TECs) cope with physiological hypoxia by focusing on the role of the Hif1a-Vhl axis. In most cell types, the oxygen-labile transcriptional regulator Hif1a is a central player in co-ordinating responses to low oxygen: under normoxic conditions Hif1a is rapidly degraded in a Vhl-guided manner; however, under hypoxic conditions Hif1a is stabilized and can execute its transcriptional functions. Unexpectedly, we find that, although TECs reside in a hypoxic microenvironment, they express little Hif1a protein and do not require Hif1a for their development or function. Instead, we find that Vhl function in TECs is vital to constrain Hif1a activity, as loss of Vhl results in dramatic defects in TEC differentiation and thymopoiesis, which can be rescued by Hif1a co-depletion.