Deletion of hypoxia-inducible factor prolyl 4-hydroxylase 2 in FoxD1-lineage mesenchymal cells leads to congenital truncal alopecia

Abstract

Hypoxia-inducible factors (HIFs) induce hundreds of genes regulating oxygen homeostasis in tissues. Oxygen sensors of the cells, the HIF prolyl 4-hydroxylases (HIF-P4Hs), regulate the stability and activity of HIFs in an oxygen-dependent manner. In this study, we show that lack of Hif-p4h-2 in FoxD1-lineage mesodermal cells interferes the normal development of hair follicles (HF) in mice. The FoxD1-lineage cells were found to be mainly mesenchymal cells located in the dermis of truncal skin, including the cells composing the dermal papilla of the HF. Upon Hif-p4h-2 inactivation, HF development was disturbed during the first catagen leading to formation of large epithelial lined HF cysts filled by unorganized keratins, which eventually manifested as truncal alopecia. The depletion of Hif-p4h-2 led to HIF stabilization and dysregulation of multiple genes involved in keratin formation, HF differentiation, and HIF, TGF{beta} and Notch signaling. The failure of the controlled process of HF cycling is likely to be mechanistically caused by disruption of the precise and timely interplay of the HIF, TGF{beta} and Notch pathways. In summary, we show here for the first time that HIF-P4H-2 function in FoxD1-lineage cells is essential for the normal development and homeostasis of HFs.