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A role for the Tgf-β/Bmp co-receptor Endoglin in the molecular oscillator that regulates the hair follicle cycle
Marı´a I. Calvo-Sa´nchez 1,2,6 , Sandra Ferna´ndez-Martos 6 , Elisa Carrasco 1 , Gema Moreno-Bueno 1,3 , Carmelo Bernabe´u 4 , Miguel Quintanilla 1 , and Jesu´s Espada 1,5,6,*
1 Instituto de Investigaciones Biome´dicas ‘Alberto Sols’, Consejo Superior de Investigaciones Cientı´ficas (CSIC)-Departamento de Bioquı´mica, Universidad Auto´noma de Madrid (UAM), Madrid 28029, Spain
2 Instituto de Investigaciones Biosanitarias, Facultad de Ciencias Experimentales, Universidad Francisco de Vitoria (UFV), Pozuelo de Alarcon 28223, Spain
3 Centro de Investigacio´n Biome´dica en Red de Ca´ncer (CIBERONC), Spain
4 Centro de Investigaciones Biolo´ gicas, Consejo Superior de Investigaciones Cientı´ficas (CSIC) and Centro de Investigacio´n Biome´dica en Red de Enfermedades Raras (CIBERER), Madrid 28040, Spain
5 Centro Integrativo de Biologı´a y Quı´mica Aplicada, Universidad Bernardo O´Higgins, Santiago 8370854, Chile
6 Present address: Instituto Ramo´n y Cajal de Investigacio´n Sanitaria (IRYCIS), Hospital Universitario Ramo´n y Cajal, Madrid, Spain *Correspondence to:Jesu´s Espada, E-mail: jespada1968@gmail.com
J Mol Cell Biol, Volume 11, Issue 1, January 2019, Pages 39-52  https://doi.org/10.1093/jmcb/mjy051
Keyword: Endoglin, hair follicle, skin stem cells, Wnt/β-catenin, Tgf-β/Bmp/Smad
The hair follicle is a biological oscillator that alternates growth, regression, and rest phases driven by the sequential activation of the proliferation/differentiation programs of resident stem cell populations. The activation of hair follicle stem cell niches and subsequent entry into the growing phase is mainly regulated by Wnt/β-catenin signalling, while regression and resting phases are mainly regulated by Tgf-β/Bmp/Smad activity. A major question still unresolved is the nature of the molecular switch that dictates the coordinated transition between both signalling pathways. Here we have focused on the role of Endoglin (Eng), a key co-receptor for members of the Tgf-β/Bmp family of growth factors. Using an Eng haploinsufficient mouse model, we report that Eng is required to maintain a correct follicle cycling pattern and for an adequate stimulation of hair follicle stem cell niches. We further report that β-catenin binds to the Eng promoter depending on Bmp signalling. Moreover, we show that β-catenin interacts with Smad4 in a Bmp/Eng-dependent context and both proteins act synergistically to activate Eng promoter transcription. These observations point to the existence of a growth/rest switching mechanism in the hair follicle that is based on an Eng-dependent feedback cross-talk between Wnt/β-catenin and Bmp/Smad signals.