Deletion of hypoxia-inducible factor prolyl 4-hydroxylase 2 inFoxD1-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, TGFβ 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, TGFβ 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.