A role for the Tgf-β/Bmp co-receptor Endoglin in the molecular oscillator that regulates the hair follicle cycle

Abstract

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 coreceptor 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 crosstalk between Wnt/β-catenin and Bmp/Smad signals. peer-reviewed)

SMAD4 Feedback Activates The Canonical TGF-β Family Signaling Pathways

“…Therefore, it is rare to identify the regulators which could mediate the downstream molecules simultaneously feedback regulation of TGF-β and BMP signaling pathways in the same cell type, tissue or during the same biological process. A recent study reported that Endoglin, a common non-canonical receptor of TGF-β and BMP signaling pathways, could regulate both of two signaling pathways [11]. However, little is known whether the core members feedback regulate these two signaling pathways.…”

“…In the nucleus, R-SMAD/SMAD4 transcription complex regulates the spatial and temporal expression of target genes, usually along with other modulators and co-regulators such as transcription factors (e.g., βcatenin [11]), transcription co-factors including co-activators (e.g., p300/CBP [36]), and co-repressors (e.g., Ski and SnoN [37]). However, the roles of SMAD4 in the interaction with these co-regulators are quite different.…”

“…Downstream signaling proteins regulate the expression of upstream signaling molecules through regulators or axes, which is the main feedback model of TGF-β family signaling pathways [6]. The regulators involved in this feedback regulation progresses includes (i) miRNAs such as SMAD4-miR-675-TGFBR1 [6], SMAD4-miR-425-TGFBR2 [7], SMAD4-miR-302-BMPR2 [8], and SMAD4-miR-24-3p-SMAD2 [9], (ii) lncRNAs such as SMAD2/3-lncRNA-MALAT1-TGFBR2 [10], (iii) transcription factors such as β-catenin (mediates SMAD4 induction of receptor) [11], and (iv) transcription co-regulators such as Snail [12].…”

Stem cell‐intrinsic mechanisms regulating adult hair follicle homeostasis

“…Surface glycoprotein endoglin (Eng) is a receptor for the Tgf‐β pathway known to modulate the crosstalk between Bmp and Wnt signalling in the hematopoietic system during early development 61,62 . Recently, it has been found to serve a similar function in HFSC during adult homeostasis, where mice with reduced whole‐body expression of Eng exhibited dissonant hair growth patterns and out‐of‐sync expressions of hair cycle regulators such as Bmp4, Noggin and Shh 63 . Further analysis revealed Wnt effector β‐catenin and Bmp effector Smad4 forming heterodimers to drive Eng expression, suggesting the communication between Wnt/β‐catenin and Tgf‐β/Bmp/Smad signalling pathways in HFSCs during homeostasis 63 …”

PTPN14, a modifier of HHT, protects SMAD4 from ubiquitination and turnover to potentiate BMP9 signaling in endothelial cells

“…It has been reported to bind several different TGFβ superfamily ligands, including BMP9 and TGFβ1 6 and it has two alternative spliced protein isoforms that differ in their short cytoplasmic tails 7 . The ENG gene is positively regulated by BMP/SMAD signaling 8–10 . Under pathological situations, such as preeclampsia or inflammation, endoglin may be shed from the cell surface by metalloproteases resulting in soluble circulating S-endoglin 11, 12 that can act as a ligand trap.…”