Molecular Genetics of the Hair Follicle: The State of the Art
M. A. M. van Steensel*,1, R. Happle and P. M. Steijlen*
Abstract :
For those who are interested in the biology of skin and its derivatives, these are interesting times indeed. In a mere 5 years, the field has been revolutionized by the application of molecular genetics to human congenital skin disorders. Where dermatology first was limited to observation and empirics, there are now DNA-diagnostics, rational drug design, and perhaps even gene therapy available soon. In particular, the study of rare human syndromes involving abnormalities of hair growth and structure has yielded new insights into the regulation of cell growth and differentiation in the hair follicle. As this structure shows a cyclic pattern of differentiation, it may give new information concerning the regulation of cell differentiation in general. This review covers the recent developments in this fast-moving field. First, we will give a short introduction to (structural) hair biology. Next, we will try to fit these data into the framework of what is already known and attempt to present a unified model for hair follicle growth and differentiation.
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“…In this model, EGF influences E-cadherin function through an Src-kinase (15). Since E-cadherin may be able to downregulate the levels of ß-catenin, it is tempting to speculate that EGF secretion by the dermal papilla modifies formation of hair follicles by the epidermis by interacting with the Wnt pathway (16). The Egf-receptor knockout mouse has, among other epithelial abnormalities, a reduced number of hair follicles. These are rudimentary and disoriented. This resembles the Lef1-knockout phenotype, supporting the notion that EGF interacts with the Wnt pathway…”
Most recently, we developed a model for skin regeneration in which hair follicles with associated stem cell populations are re-formed following wounding in mice. The new follicles form de novo and function normally. Intriguingly, they do not arise from preexisting hair follicle stem cells, but rather from non-bulge basal keratinocytes. Our research focuses on understanding the molecular signals involved in the transition of epidermal cells to hair follicle stem cells."
PLoS ONE. 2008 ;3 (6):e2471 18560570 (P,S,G,E,B,D) Binding of sFRP-3 to EGF in the Extra-Cellular Space Affects Proliferation, Differentiation and Morphogenetic Events Regulated by the Two Molecules.
[My paper] Raffaella Scardigli, Cesare Gargioli, Daniela Tosoni, Ugo Borello, Maurilio Sampaolesi, Clara Sciorati, Stefano Cannata, Emilio Clementi, Silvia Brunelli, Giulio Cossu
Department of Developmental Biology, Institute of Cell Biology and Tissue Engineering, San Raffaele Biomedical Science Park of Rome, Rome, Italy.
BACKGROUND: sFRP-3 is a soluble antagonist of Wnts, widely expressed in developing embryos. The Wnt gene family comprises cysteine-rich secreted ligands that regulate cell proliferation, differentiation, organogenesis and oncogenesis of different organisms ranging from worms to mammals. In the canonical signal transduction pathway Wnt proteins bind to the extracellular domain of Frizzled receptors and consequently recruit Dishevelled (Dsh) to the cell membrane. In addition to Wnt membrane receptors belonging to the Frizzled family, several other molecules have been described which share homology in the CRD domain and lack the putative trans-membrane domain, such as sFRP molecules (soluble Frizzled Related Protein). Among them, sFRP-3 was originally isolated from bovine articular cartilage and also as a component of the Spemann organizer. sFRP-3 blocks Wnt-8 induced axis duplication in Xenopus embryos and binds to the surface of cells expressing a membrane-anchored form of Wnt-1. Injection of sFRP-3 mRNA blocks expression of XMyoD mRNA and leads to embryos with enlarged heads and shortened trunks. METHODOLOGY/PRINCIPAL FINDINGS: Here we report that sFRP-3 specifically blocks EGF-induced fibroblast proliferation and foci formation. Over-expression of sFRP-3 reverts EGF-mediated inhibition of hair follicle development in the mouse ectoderm while its ablation in Xenopus maintains EGF-mediated inhibition of ectoderm differentiation. Conversely, over-expression of EGF reverts the inhibition of somitic myogenesis and axis truncation in Xenopus and mouse embryos caused by sFRP-3. In vitro experiments demonstrated a direct binding of EGF to sFRP-3 both on heparin and on the surface of CHO cells where the molecule had been membrane anchored. CONCLUSIONS/SIGNIFICANCE: sFRP-3 and EGF reciprocally inhibit their effects on cell proliferation, differentiation and morphogenesis and indeed are expressed in contiguous domains of the embryo, suggesting that in addition to their canonical ligands (Wnt and EGF receptor, respectively) these molecules bind to each other and regulate their activities during embryogenesis.
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