Inflammatory mediator TAK1 regulates hair follicle morphogenesis and anagen induction shown by using keratinocyte-specific TAK1-deficient mice.
Transforming growth factor-beta-activated kinase 1 (TAK1) is a member of the NF-kappaB pathway and regulates inflammatory responses. We previously showed that TAK1 also regulates keratinocyte growth, differentiation, and apoptosis. However, it is unknown whether TAK1 has any role in epithelial-mesenchymal interactions. To examine this possibility, we studied the role of TAK1 in mouse hair follicle development and cycling as an instructive model system. By comparing keratinocyte-specific TAK1-deficient mice (Map3k7(fl/fl)K5-Cre) with control mice, we found that the number of hair germs (hair follicles precursors) in Map3k7(fl/fl)K5-Cre mice was significantly reduced at E15.5, and that subsequent hair follicle morphogenesis was retarded. Next, we analyzed the role of TAK1 in the cyclic remodeling in follicles by analyzing hair cycle progression in mice with a tamoxifen-inducible keratinocyte-specific TAK1 deficiency (Map3k7(fl/fl)K14-Cre-ER(T2)). After active hair growth (anagen) was induced by depilation, TAK1 was deleted by topical tamoxifen application. This resulted in significantly retarded anagen development in TAK1-deficient mice. Deletion of TAK1 in hair follicles that were already in anagen induced premature, apoptosis-driven hair follicle regression, along with hair follicle damage. These studies provide the first evidence that the inflammatory mediator TAK1 regulates hair follicle induction and morphogenesis, and is required for anagen induction and anagen maintenance.
Sayama
Koji
K
Department of Dermatology, Ehime University Graduate School of Medicine, Ehime, Japan. sayama@m.ehime-u.ac.jp
Kajiya
Kentaro
K
Sugawara
Koji
K
Sato
Shintaro
S
Hirakawa
Satoshi
S
Shirakata
Yuji
Y
Hanakawa
Yasushi
Y
Dai
Xiuju
X
Ishimatsu-Tsuji
Yumiko
Y
Metzger
Daniel
D
Chambon
Pierre
P
Akira
Shizuo
S
Paus
Ralf
R
Kishimoto
Jiro
J
Hashimoto
Koji
K
D000818:Animals; D006197:Hair / Q000254:growth & development*; D015603:Keratinocytes / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009024:Morphogenesis; D000099151:MAP Kinase Kinase Kinase 7
D020930:MAP Kinase Kinase Kinases; D000099151:MAP Kinase Kinase Kinase 7