Hair morphogenesis and what controls it

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Molecular controls of hair morphogenesis

The hair follicle morphogenesis is the sum total of some developmental events. They are controlled by a complex network of sequential activation and inactivation of autocrine, paracrine, and endocrine signalling pathways. Multiple regulatory factors have been identified in the recent times and the essential natures of their influence on hair follicle development have also been sorted out. However there are certain areas where the scientists are still in dark---they include the questions such as how these regulators interact with each other, their relative significance, the degree of redundancy in the signalling system, and how these signals determine the development of such a complex structure, its size, and subsequent growth cycle characteristics.

What triggers the initial signal for hair follicle development remains unproven. According to currently evidences, the first signal emanates from the embryonic mesoderm. Again it is unclear whether the epithelium plays a purely passive role in the induction of the first signal. The earliest known molecular pathway activated during hair follicle development involves ß-catenin, an intracellular mediator of gene expression. Research has established the ß-catenin’s essential role for keratinocyte stem cell fate decision. Over-expression of stabilized ß-catenin in the epidermis of transgenic mice has been shown to induce de-novo hair follicle morphogenesis demonstrating its fundamental importance in hair follicle development. Contrastingly, the absence of functional ß-catenin is marked by keratinocytes differentiating to an epidermal role and a failure of hair follicle development.

Products of the WNT gene family are secreted glycoproteins that regulate cell proliferation, migration and specification of cell fate in the embryo and adult. Classification of WNT proteins are made according to their ability to promote stabilization and prevent degradation of ß-catenin in the cell cytoplasm. WNT pathway that is dependent on the ß-catenin, signals through cytoplasmic stabilization and accumulation of ß-catenin. It accumulates and translocates to the cell nucleus to form complexes with members of the lymphoid enhancer-binding factor/T cell factor (LEF/TCF) family of DNA binding factors to activate gene transcription. The successful induction of hair follicle development in mice was made possible by activation of WNT signalling in the skin. At this stage of hair follicle embryogenesis, WNT gene coded proteins are the first extracellular mediators known to be involved in hair follicle development. However, scientists do not rule out the possibility of an even earlier gene coded signaling mechanism that activates hair follicle development and promotes WNT gene signaling.

A plethora of extracellular and intracellular mediators starts getting expressed with the initiation of the first signaling and placode formation. WNT signals transduced by ß-catenin and LEF-1, can elicit expression of ectodysplasin A (EDA). Experimentally, expression of, EDA, activation of its receptor, EDAR, or subsequent downstream activation of the NF-kB pathway mediated by EDAR, will each lead to hair follicle development. Not surprisingly, expression of LEF1 will also induce hair follicle formation as will expression of Noggin, TGFß2, TGFßR-II, ß1 integrin and NCAM. Fibroblast growth factors FGF1, FGF2, FGF4, and receptor FGFr2 may also have a hair follicle inductive role based on studies with chick embryos and promotion of feather formation. Contrastingly, multiple inhibitors of hair follicle placode formation, including BMP-2, BMP-4, p75NTR and activin ?a are also expressed in the embryonic skin. Now the signalling scheme is already crowded. To this crowd are added the genes encoding several secreted molecules capable of inhibiting the inhibitors of hair follicle induction, including Noggin, Follistatin, and Gremlin, which are also expressed in developing follicles. This apparently very complex interplay between activators and inhibitors of hair follicle formation, along with the respective regulators of activator and inhibitor product expression, determine the distribution of follicles in the skin.

In the middle of the development of hair follicles, yet more factors are required to regulate the hair germ in its growth and differentiation. Ectodermal cells of the developing hair follicle secrete PDGFA and Sonic hedgehog (Shh) which are required for the condensation of the presumptive dermal papilla cells and for the progression of the follicle placode to the peg/bulge hair stages. Asymmetric expression of Shh also polarizes the hair ensuring outgrowth of the hair follicle in a defined direction. The activin ?a can act as a placode inhibitor. On the other hand activin ?a acts as driving factors during organogenesis along with Shh, HGF/MET, SOX18, and TGFa. These along with other products propel the down-growth of the hair germ into the dermis. The 5th to 8th stage of hair follicle morphogenesis, make the follicle differentiate into the complex structures comprising a mature hair follicle. Still there are more signalling pathways and product expression that are involved in this process including Notch1, KGF, nude, BMP2, BMP4, MOVO1, multiple HOX genes and again, mediators such as WNT gene products and their transcriptional activators such as LEF1. The precise interactions between all these signaling events are not yet clearly defined.

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