Abstract
Hair follicle morphogenesis depends on Wnt, Shh, Notch, BMP and other signaling pathways interplay between epithelial and mesenchymal cells. The Wnt pathway plays an essential role during hair follicle induction, Shh is involved in morphogenesis and late stage differentiation, Notch signaling determines stem cell fate while BMP is involved in cellular differentiation. The Wnt pathway is considered to be the master regulator during hair follicle morphogenesis. Wnt signaling proceeds through EDA/EDAR/NF-κB signaling. NF-κB regulates the Wnt pathway and acts as a signal mediator by upregulating the expression of Shh ligand. Signal crosstalk between epithelial and mesenchymal cells takes place mainly through primary cilia. Primary cilia formation is initiated with epithelial laminin-511 interaction with dermal β-1 integrin, which also upregulates expression of downstream effectors of Shh pathway in dermal lineage. PDGF signal transduction essential for crosstalk is mediated through epithelial PDGF-A and PDGFRα expressed on the primary cilia. Dermal Shh and PDGF signaling up-regulates dermal noggin expression; noggin is a potent inhibitor of BMP signaling which helps in counteracting BMP mediated β-catenin inhibition. This interplay of signaling between the epithelial and dermal lineage helps in epithelial Shh signal amplification. The dermal Wnt pathway helps in upregulation of epithelial Notch expression. Dysregulation of these pathways leads to certain abnormalities and in some cases even tumor outgrowth.
Highlights
The hair follicle (HF) is considered a mini-organ formed with neuroectodermal-mesodermal interaction [1]
Sonic hedgehog (Shh) signaling is dispensable for HF induction but it is required for epithelial proliferation and hair placode down growth [65,88,89]
The question is, where do the signals driving the tumors come from? What type of mutations occurs in genes and when do they happen? Are all the cells in a tumor involved in its growth ? How are basic mechanisms of HF regeneration involved in tumorigenesis? What is the role of niche signaling in regulation of tumor growth? Can certain tumors be suppressed by turning off particular signaling pathways? Should different tumors be treated in different ways? there are many questions left unanswered in tumor biology, recent progress has refined knowledge concerning the role of signaling pathways involved in tumorigenesis
Summary
The hair follicle (HF) is considered a mini-organ formed with neuroectodermal-mesodermal interaction [1]. Wnt mediated signal transduction first arises in mesenchymal cells directing the thickening of overlying epithelial cells to form a placode. The organogenesis stage consists of complex interplay of signals; epithelial cells direct the underlying dermal cells to proliferate and form a dermal condensate, which in turn signals the epithelial cells to proliferate and grow downwards into the dermis. The cycle includes anagen (growth phase), catagen (regression phase) and telogen (resting phase); exogen (release of the telogen club or hair shredding) does not occur at every cycle [3]. Club shaped bulb indicates attainment of the hair shaft (HS) differentiation; catagen is followed by a resting phase known as telogen [3]. Telogen to anagen transition is dependent upon many factors and since during the telogen phase the HF strongly expresses estrogen receptors, the binding of 17-β-estradiol to these receptors prevents HFs from exiting the telogen phase to enter anagen phase [8]
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