Signaling involved in hair follicle morphogenesis and development

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.

Figure 1.

Hair anatomy. The hair root comprises a hair follicle (HF), a hair bulb, and a dermal papilla (DP). The outer root sheath (ORS) is a direct continuation of the Malpighian layer of the epidermis. The bulge (B) is located at the insertion site of the arrector pili muscle (APM) into the ORS. The insertion of the sebaceous gland (SG) duct forms the anatomical interface between the infundibulum and isthmus. A dotted line separates an upper transient portion of the hair from a lower permanent portion. IRS, inner root sheath; m, matrix; HS, hair shaft.

Figure 2.

Stages of hair follicle morphogenesis. HFs are formed by interaction between epithelium (keratinocytes) and underlying dermal fibroblasts. Comprehensive lists of signaling molecules (capitals) and transcription factors (italics) are provided for each stage. Signaling molecules and pathways indicated in black are either expressed or activated in keratinocytes while grey ones are associated with dermal fibroblasts.