Abstract
Hypoxia-inducible factors (HIFs) induce numerous genes regulating oxygen homeostasis. As oxygen sensors of the cells, the HIF prolyl 4-hydroxylases (HIF-P4Hs) regulate the stability of HIFs in an oxygen-dependent manner. During hair follicle (HF) morphogenesis and cycling, the location of dermal papilla (DP) alternates between the dermis and hypodermis and results in varying oxygen levels for the DP cells. These cells are known to express hypoxia-inducible genes, but the role of the hypoxia response pathway in HF development and homeostasis has not been studied. Using conditional gene targeting and analysis of hair morphogenesis, we show here that lack of Hif-p4h-2 in Forkhead box D1 (FoxD1)-lineage mesodermal cells interferes with the normal HF development in mice. FoxD1-lineage cells were found to be mainly mesenchymal cells located in the dermis of truncal skin, including those cells composing the DP of HFs. We found that upon Hif-p4h-2 inactivation, HF development was disturbed during the first catagen leading to formation of epithelial-lined HF cysts filled by unorganized keratins, which eventually manifested as truncal alopecia. Furthermore, the depletion of Hif-p4h-2 led to HIF stabilization and dysregulation of multiple genes involved in keratin formation, HF differentiation, and HIF, transforming growth factor β (TGF-β), and Notch signaling. We hypothesize that the failure of HF cycling is likely to be mechanistically caused by disruption of the interplay of the HIF, TGF-β, 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.
Highlights
Cells have an intrinsic response to low O2 concentrations that is controlled by the hypoxia-inducible transcription factor (HIF, αβ dimers)
We examined whether inactivation of Hif-p4h-2 in the dermal papilla (DP) cells affects their communication with the bulge stem cell (SC), which could result in the interruption of the development of the hair follicle (HF) and subsequent cyst formation
We show here for the first time that inactivation of the main oxygen sensor hypoxia-inducible factor (HIF)-prolyl 4-hydroxylase (P4H)-2 in Forkhead box D1 (FoxD1)-lineage cells disrupts normal HF development and cycling
Summary
Inactivation of Hif-p4h-2 in FoxD1-lineage dermal cells results in truncal congenital alopecia. At the end of the catagen (P18), a strong upregulation of Kgf expression was observed in the cKO mice relative to control, which later at P21 and P24 converted to a marked downregulation of the Kgf mRNA (Fig. 5C) This indicates that the initiation of the anagen phase by the cKO DP cells in the cyst bulge SCs is disturbed. The Krt mRNA level was significantly higher at P14 in the cKO skin, whereas during the HF catagen and telogen (P16–P21), the level was significantly reduced relative to controls (Fig. 5C) These data suggest that the bulge SC population is abnormally distributed in the cKO mice, causing interference in the signaling from the DP cells to the bulge SCs. Transmission electron microscopy (TEM) revealed that formation of both the hair shaft and the HF was disturbed in the cKO mice. The data suggest that Notch signaling homeostasis is disturbed in the cKO mice
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