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

Abstract

We aimed to investigate how the depletion of hypoxia inducible factor prolyl-4 hydroxylase 2 (HIF- P4H-2) in Forkhead Box D1 (FoxD1) lineage cells affects hair follicle (HF) and skin development. Hypoxia-inducible factors (HIFs) induce hundreds of genes regulating oxygen homeostasis in tissues. The HIF-P4Hs regulate the stability and hence the activity of HIFs in an oxygen-dependent manner. The skin is a hypoxic organ with endogenous HIF expression but the role of hypoxia signalling in skin and HFs are poorly understood. We studied a mouse line where Hif-p4h-2 is conditionally inactivated in FoxD1-expressing (FoxD1+) cells. This mouseline was studied at different developmental stages during the HF morphogenesis and cycle. To be able to pinpoint the location of FoxD1+ cells we studied the skin of a mouse line where FoxD1+ cells could be seen due to the expression of enhanced green fluorescent protein and the non-FoxD1-expressing cells due to the expression of tomato-red. Lack of Hif-p4h-2 in FoxD1-lineage mesodermal cells causes disturbed HF development during the first catagen leading to formation of large epithelial lined HF cysts filled with keratins, which eventually manifests as truncal alopecia. The cranial hair remains normal. We show that FoxD1+ cells are mesenchymal cells located in the dermis and dermal papilla of truncal skin. FoxD1+ cells are scarce in the cranial skin. The depletion of Hif-p4h-2 in FoxD1+ cells misregulates genes crucial for hypoxia response, keratin formation and differentiation, TGF-β and Notch signalling pathways, which are known to be essential for the HF development and cycling. 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.