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Formation of Mammalian Hair

The mammalian hair follicle is a dynamic structure that generates a hair shaft through a tightly controlled cycle of growth, remodeling, and loss. Once a hair follicle is made, it can undergo many of these cycles, continually making, growing, and losing the hair shaft. In mammals, the cycle of hair growth includes three stages: anagen (follicle generation and hair production), catagen (follicle regression), and telogen (resting phase). A commercial site describes this cycle of hair regeneration.

The production of the follicle is an extremely complicated event, and literally dozens of genes are known to play roles in its formation. We can only discuss a few of them here. Like the kidney, tooth, and the eye, there are reciprocal inductions. In this case, the developmental dialogue involves the epidermal cells of the skin (an ectodermal epithelium) and the dermal cells beneath it (a mesodermal mesenchyme). The progression of the developmental dialogue for hair formation has recently been summarized by Philpott and Paus (1998) and Müller-Röver and Paus, 1998).

Initial inductive events

These events are summarized in Figure 1 and in a commercial website for hairgrowth products.

Figure 1
Figure 1   Early development of the hair follicle and primitive hair shaft. (A) Initial state of epidermal epithelium atop dermal mesenchyme. (B) Signal (probably from mesenenchyme) initiates local proliferation of the basal keratinocytes (epidermal stem cells) in the epidermis. (C) Proliferation of epidermal stem cells results in the formation of the hair germ, which signals the dermal mesenchymal cells to aggregate beneath it into a dermal papilla. (D) The papilla signals the continued proliferation of the hair germ, making it into a hair peg (or primitive hair shaft). The dermal papilla cells proliferate and tightly aggregate. (E) The primitive hair shaft engulfs the dermal papilla and forms the inner hair root directly above the papilla. (After Philpott and Paus, 1998.)

Differentiation of the hair shaft

The next stages involve the differentiation of the hair shaft. The epidermal hair germ is surrounded by mesoderm. At its base is the dermal papilla. On its sides are less condensed mesenchyme, which, nevertheless, had been part of the original dermal papilla. During anagen, pluripotent epidermal matrix cells in the hair bulb move upward. Their cell fate is specified by their initial positioning relative to the dermal papilla at the base of the follicle (Chase, 1954; Millar et al., 1999). Cells at the center of the follicle become the medulla (center) of the hair shaft, while slightly more marginal cells become the cortex and cuticle of the hair shaft. Even more peripheral cells, those cells differentiating at the base of the dermal papilla (near where it meets the tip of the ectoderm), differentiate into the inner root sheath.

This later stage of hair development is illustrated in Figure 2.

Figure 2
Figure 2   Differentiation of the hair shaft. (A) Elongation of the inner root sheath about halfway up the hair follicle. Sebaceous cells and bulge appear, as melanin granules enter into the cortex. (B) Follicle growth altered to about 60 degrees to the epidermis. Sebaceous glands form and the hair canal is made. The hair shaft differentiates the inner root sheath of epidermal cells. (C) Sebaceous gland becomes localized on the lateral wall of the follicle, while the hair shaft extends into the hair canal. (D) Hair shaft extends out past the skin. (After Philpott and Paus, 1998.)

Hair placement and growth

It is not known why certain regions of the body are allowed to have hair and other regions are not. It is also not known why the hair on our scalp and chin is allowed to grow continuously and become long, while our armpit hair, eyebrows, and pubic hair never grow past a certain length. The regionalization of the dermis may have something to do with this, but what the dermis does is not known.

Hypertrichosis

However, there are some individuals whose hair growth and placement are genetically altered. A striking (at least to us humans) mutation involving hair growth is congenital generalized hypertrichosis. This very rare X-linked dominant condition is characterized by excessive facial and upper torso hair in males and by a less severe asymmetric hairiness in females. The people who have this condition have hair placement more typical of mammals in general, and less typical of the human hair placement. (Indeed, it has led to such people being exhibited in side-shows as "dog man," "the human terrier," "werewolf" and other such designations.) Figuera and colleagues (1995) have been mapping this gene and showed that it is on the long arm of the X chromosome, between Xq24-Xq27. This is the first example of a gene that may be involved in the regulation of human hair growth to certain regions of the body (Figure 3).

Figure 3
Figure 3   A 6-year-old boy with congenital generalized hypertrichosis. (From Figuera et al., 1995.)

FGF5. In mice, the coat hair has a genetically defined length. (Mice don't need haircuts). This length can be altered by the angora mutation. The angora mouse mutant has abnormally long hair, due to an increase in the time that the follicles remain in the anagen phase of this cycle (Pennycuik and Raphael, 1984). This condition is due to mutations in the gene for fibroblast growth factor 5 (FGF5), which is expressed in the outer root sheath of the hair follicle (Hébert et al., 1994). FGF-5 appears to be needed for the progression of the hair cycle from the anagen stage to the catagen stage. Without FGF-5, this time is delayed and the hair shaft keeps growing. Eventually, the catagenic stage is reached, perhaps because the hair matrix cells have only a limited capacity for proliferation or perhaps because another FGF molecule can substitute at a lower efficiency.

WNT3. The paracrine factor Wnt3 may also be involved in regulating the limits of hair growth. Wnt3 is expressed (in both developing and mature hair follicles) in the matrix cells that will become the medulla of the hair shaft. Overexpression of Wnt3 in transgenic mouse skin causes a short-hair phenotype (Millar et al., 1999). This shortening of the hair is caused by the altered differentiation of hair shaft precursor cells. A putative effector molecule for WNT3 signaling, the cytoplasmic protein Dishevelled-2, is normally present at high levels in a subset of cells in the outer root sheath and in precursor cells of the hair shaft cortex and cuticle which lie immediately to the lateral sides of the Wnt3-expressing cells. Overexpression of Dishevelled-2 in the outer root sheath mimics the short-hair phenotype produced by overexpression of Wnt3.

Literature Cited

Chase, H. B. 1954. Growth of the hair. Physiol. Rev. 34: 113-126.

Figuera, L. E., Pandolfo, M., Dunne, P. W., Cantú, J., and Patel, P. I. 1995. Mapping of the congenital generalized hypertrichosis locus to chromosome Xq24-q27.1. Nature Genet. 10: 202-207.

Hébert, J. M., Rosenquist, T., Götz, J., and Martin, G. R. 1994. FGF5 as a regulator of the hair growth cycle: Evidence from targeted and spontaneous mutations. Cell 78: 1017-1025.

Millar, S. E., Willert, K., Salinas, P. C., Roelink, H., Nusse, R., Sussman, D. J., and Barsh, G. S. WNT signaling in the control of hair growth and structure. Dev. Biol. 207: 133-149.

Müller-Röver, S. and Paus, R, 1998. Topobiology of the hair follicle: Adhesion molecules as morphoregulatory signals during hair follicle morphogenesis. In Chuong, C.-M. (ed.) Molecular Basis of Epithelial Appendage Morphogenesis. R. G. Landes, Austin. Pp. 283-314.

Pennycuik, P. R. and Raphael, K. A. 1984. The angora locus (go) in the mouse: hair morphology, duration of growth cycle, and site of action. Genet. Res. 44: 283-291.

Philpott, M. and Paus, R. 1998. Principles of hair follicle morphogenesis. In Chuong, C.-M. (ed.) Molecular Basis of Epithelial Appendage Morphogenesis. R. G. Landes, Austin. Pp. 75-110.

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