Androgenetic alopecia is a common form of pattern hair loss, characterized by miniaturized hair follicles (HFs) at the front and parietal scalp, while hairs on the occipital scalp are preserved. Moreover, different body sites exhibit distinct types and patterns of HFs and understanding the molecular basis for this heterogeneity is important to design targeted treatment strategies. The Wnt signalling pathway and its Dickkopf (Dkk) inhibitors have been suggested to regulate HF type and patterning. We have previously shown that Dkk4 is specifically expressed in the epithelial placodes of HFs during mouse skin development. To elucidate the functions of Dkk4 in HF patterning, in this work, we used CRISPR/Cas9 to generate Dkk4-knockout mice. Dkk4 mutants showed disrupted HF patterning where the interplacodal distance was increased. Surprisingly, the lateral back skin of Dkk4 mutants was completely devoid of the first wave of HFs. In order to address the heterogeneity and regional differences in HF formation, we generated a Dkk4-EGFP knockin mouse line, which recapitulated the expression of Dkk4 in HF placodes. Our data revealed intra-and interplacodal differences in the expression of Dkk4-EGFP, suggesting that a WNT-DKK axis underlies the regional specificities in HF induction and patterning. Elucidating the molecular mechanisms of this heterogeneity will shed light on hair loss patterns such as in androgenetic alopecia.

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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.