323 Human Long-Term Deregulated Circadian Rhythm Alters Regernerative Properties of Skin and Hair Precursor Cells

Abstract

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.