Brief report: requirement of TACE/ADAM17 for hair follicle bulge niche establishment.
Hair follicles (HFs) are equipped with stem cell niches that allow regeneration. Tumor necrosis factor-α converting enzyme (TACE), also known as A disintegrin and metalloproteinase 17, is a proteolytic enzyme that regulates a variety of cell surface molecules including TNF-α, via ectodomain shedding. We found TACE expression on mouse HFs and conditionally depleted it in cells that expressed sex-determining region Y-related high-mobility-group box 9 (SOX9) transcription factor, an HF stem cell transcription factor (Tace(flox/flox) -Sox9-Cre, hereafter, "Tace/Sox9"). Tace/Sox9 mice were born with brittle hair with prolonged anagen phase. They underwent diffuse, progressive, and ultimately whole-body hair loss by 20 weeks old. Tace/Sox9 HFs lacked CD34(+) bulge cells as demonstrated via immunofluorescence microscopy and flow cytometry. Real-time PCR revealed downregulation of transcription factors Sox9, Lhx2, and Gata3 and upregulation of Lef1. In vitro colony-forming capacity was abolished in Tace/Sox9 keratinocytes, and HFs exhibited increased proliferation in situ, collectively demonstrating that Tace/Sox9 mice failed to establish the bulge niche and to maintain "stemness" of HF stem cells. Epidermal growth factor receptor (EGFR) signaling was impaired in Tace/Sox9 keratinocytes, and mice depleted of Egfr in SOX9-expressing tissues exhibited hair phenotype nearly identical to Tace/Sox9 mice, demonstrating EGFR signaling as a pathway downstream of TACE in HF homeostasis. This study provides mechanistic implication for human TACE-deficiency and for hair abnormality caused by EGFR inhibitors.
Department of Dermatology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan. nagaok@med.keio.ac.jp
Keisuke
K
Nagao
Tetsuro
T
Kobayashi
Manabu
M
Ohyama
Haruhiko
H
Akiyama
Keisuke
K
Horiuchi
Masayuki
M
Amagai
D051722:ADAM Proteins / Q000378:metabolism*; D000072198:ADAM17 Protein; D000505:Alopecia / Q000378:metabolism*; D000818:Animals; D006197:Hair / Q000378:metabolism; D018859:Hair Follicle / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D015398:Signal Transduction; D055153:Stem Cell Niche / Q000502:physiology*
D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse