The Tgf-β/Bmp Co-Receptor Endoglin Is a Key Component of the Molecular Oscillator That Regulates the Hair Follicle Cycle

The hair follicle is a biological oscillator that sequentially alternates phases of growth, regression and rest. The cyclic activity of this oscillator is driven by a stem cell population regulated by nurse cells and located in the hair follicle bulge region. As a whole, this morpho‐functional structure constitutes a suitable model to study the dynamics of the stem cell niches that actually maintain homeostatic and regeneration processes during development and in adult tissues. In the hair follicle, the activation of the stem cell niche 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 transition between both signalling pathways during the hair follicle growth cycle. 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 a haploinsufficient mouse model we have demonstrated that Eng is required for the stimulation of the hair follicle stem cell niche and to maintain a correct follicle cycling pattern. We further report that β‐catenin binds to the Eng promoter depending on Bmp signalling. Moreover, 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 crosstalk between Wnt/β‐ catenin and Bmp/Smad signals.