P-cadherin regulates human hair growth and cycling via canonical Wnt signaling and transforming growth factor-β2.
P-cadherin is a key component of epithelial adherens junctions, and it is prominently expressed in the hair follicle (HF) matrix. Loss-of-function mutations in CDH3, which encodes P-cadherin, result in hypotrichosis with juvenile macular dystrophy (HJMD), an autosomal recessive disorder featuring sparse and short hair. Here, we attempted to recapitulate some aspects of HJMD in vitro by transfecting normal, organ-cultured human scalp HFs with lipofectamine and CDH3-specific or scrambled control siRNAs. As in HJMD patients, P-cadherin silencing inhibited hair shaft growth, prematurely induced HF regression (catagen), and inhibited hair matrix keratinocyte proliferation. In situ, membrane β-catenin expression and transcription of the β-catenin target gene, axin2, were significantly reduced, whereas glycogen synthase kinase 3 β (GSK3β) and phospho-β-catenin immunoreactivity were increased. These effects were partially reversed by inhibiting GSK3β. P-cadherin silencing reduced the expression of the anagen-promoting growth factor, IGF-1, whereas that of transforming growth factor β 2 (TGFβ2; catagen promoter) was enhanced. Neutralizing TGFβ antagonized the catagen-promoting effects of P-cadherin silencing. In summary, we introduce human HFs as an attractive preclinical model for studying the functions of P-cadherin in human epithelial biology and pathology. This model demonstrates that cadherins can be successfully knocked down in an intact human organ in vitro, and shows that P-cadherin is needed for anagen maintenance by regulating canonical Wnt signaling and suppressing TGFβ2.
Department of Dermatology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel; Department of Dermatology, University of Luebeck, Luebeck, Germany.
Liat
L
Samuelov
Department of Dermatology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel; Department of Human Molecular Genetics & Biochemistry, Sackler Faculty of Medicine, Tel-Aviv University, Ramat Aviv, Israel.
Eli
E
Sprecher
Department of Dermatology, University of Kurume, Kurume, Japan.
Daisuke
D
Tsuruta
DE-MTA "Lendulet" Cellular Physiology Group, Department of Physiology, University of Debrecen, Debrecen, Hungary.
Tamás
T
Bíró
Department of Dermatology, University of Luebeck, Luebeck, Germany.
Jennifer E
JE
Kloepper
Department of Dermatology, University of Luebeck, Luebeck, Germany; School of Translational Medicine, University of Manchester, Manchester, UK. Electronic address: ralf.paus@uksh.de.
Ralf
R
Paus
D000328:Adult; D015820:Cadherins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle / Q000502:physiology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D015897:Comorbidity; D005260:Female; D020868:Gene Silencing / Q000187:drug effects; D006197:Hair / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism*; D018859:Hair Follicle / Q000166:cytology / Q000254:growth & development; D006801:Humans; D007039:Hypotrichosis / Q000453:epidemiology / Q000209:etiology / Q000503:physiopathology; D066298:In Vitro Techniques; D008268:Macular Degeneration / Q000453:epidemiology / Q000209:etiology / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D034741:RNA, Small Interfering / Q000494:pharmacology; D014162:Transfection; D053781:Transforming Growth Factor beta2 / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000502:physiology*
C512197:CDH3 protein, human; D015820:Cadherins; D034741:RNA, Small Interfering; D053781:Transforming Growth Factor beta2