The role of the hairless (hr) gene in the regulation of hair follicle catagen transformation - PubMed (original) (raw)

The role of the hairless (hr) gene in the regulation of hair follicle catagen transformation

A A Panteleyev et al. Am J Pathol. 1999 Jul.

Abstract

Mice that carry a mutation at the hairless (hr) locus develop seemingly normal hair follicles (HF) but shed their hairs completely soon after birth. Histologically, their HFs degenerate into characteristic utriculi and dermal cysts shortly after the entry of the HF into the first regression phase (catagen), during the initiation of HF cycling. Here, we show that at least nine distinct stages of HF disintegration can be distinguished in hr/hr mice. Toward the end of HF morphogenesis (day 15 postpartum) the proximal hair bulb in hr/hr skin undergoes premature and massive apoptosis. This is associated with a dyscoordination of cell proliferation in defined HF compartments, malpositioning of the proximal inner root sheath, striking atrophy of outer root sheath, and failure of trichilemmal keratinization in the developing club hair. Rather than undergoing their normal catagen-associated involution, the hair bulb and central outer root sheath disintegrate into separate cell clusters, thus disrupting all epithelial contact with the dermal papilla. Dermal papilla fibroblasts fail to migrate upward, and break up into clusters of shrunken cells stranded in the reticular dermis as dermal cyst precursors, while the upper HF epithelium transforms into utriculi. Some dermal papilla cells, which normally never undergo apoptosis, also become TUNEL+ in hr/hr skin, and their normally high expression of a key adhesion molecule, neural cell adhesion molecule, declines. Thus, loss of a functional hr gene product (a putative zinc finger transcription factor) initiates a premature, highly dysregulated catagen, which results in the destruction of the normal HF architecture and abrogates the HF's ability to cycle. This provides new insights into the pathobiology of the hr mutation, and suggests that the normal hr gene product is a crucial element of catagen control.

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Figures

Figure 1.

Figure 1.

Progression of hair loss in hr/hr mice. A: Initial stage of hair loss in hr/hr pups (day 14 pp). Note the alopecic skin around the eyes and on the forelimbs. B: hr/hr pups at different stages of hair shedding (days 16–21 pp). C: Scheme of progression of the wave of hair shedding in hr/hr mice. The reference area examined (hatched) was located on the upper back. All stages of HF transformation were observed in this area during days 15–18 of mouse postnatal development.

Figure 2.

Figure 2.

Schematic representation of HF disintegration in hr/hr skin. The apparently normal HF at anagen VI stage (day 14 pp) is shown. Its subsequent transformation can be divided into 9 successive stages, as outlined below. 1: The HF in hr/hr skin appear normal. However, the hair canals (hc) are significantly widened as compared to +/hr littermates. 2: The hair shaft (hse) looses its connection with the hair bulb. The follicle above the hair bulb narrows and becomes curved, lacking its normal hair shaft content. 3: The hair bulb shrinks abruptly. The proximal inner root sheath (irs) does not shorten, and therefore terminates below the end of the hair shaft. The hair canals gradually widen further and form ampulliform structures (as). 4: The hair bulb disappears and the dermal papilla (DP) is nearly devoid of a surrounding epithelium, however, it is still encased by the perifollicular connective tissue sheath (cts). The HF portion between the DP and the proximal end of the hair shaft forms a narrow, curved strand of epithelial cells (es). The proximal part of the IRS coalesces around the end of the hair shaft. The club hair (ch) starts to form, however, it displays an abnormally rounded and irregular shape. 5: The epithelial strand begins to break up into separate cell clusters (sr), surrounded by a thin layer of connective tissue sheath. The DP loses its connection with the proximal HF epithelium. A thick and prominent IRS retains the hair shaft in its follicular mooring. 6: The IRS abruptly disintegrates, resulting in rapid upward movement of the hair shaft. The DP remains in the deep dermis, surrounded by a few epithelial cells. 7: The abnormally large and bulbous club hair (ch) that lacks normal spiculae is mechanically retained in the zone of trichilemmal keratinization (tk). 8: Further widening of the pilary canal and complete regression of the ORS allows the hair club to pass through the zone of the trichilemmal comb, and the hair shaft falls out. The characteristic utriculi (u) of hr/hr skin form. 9: Only a small cluster of epithelial cells (putative bulge-derived cells, pbdc) remains in contact with the utricle and arrector pili muscle (m). The sebaceous gland gradually surrounds PBDC clusters to form a circular structure. The epithelial cells that remain in contact with dermal papilla start to proliferate (Ki-67 positivity). as, ampulliform dilatation of hair canal; bg, bulge; ch, club hair; cts, connective tissue sheath; dp, dermal papilla; dpr, dermal papilla remnant; er, epithelial remnant of ORS; es, epithelial strand; hc, hair canal; hs, hair shaft; hse, hair shaft end; irs, inner root sheath; m, arrector pili muscle; ors, outer root sheath; pbdc, putative bulge-derived cells; sg, sebaceous gland; sr, strand remnants; tk trichilemmal keratinization; u, utricle.

Figure 3.

Figure 3.

The process of HF disintegration in hr/hr skin. A: The HF infundibulum in hr/hr skin at stage 1 of hairless phenotype formation (day 14 pp). The dilation of the HF infundibulum starts from its most distal portion (arrowhead) adjacent to the epidermis (e). B: The HF infundibulum in +/hr skin (control littermates) at day 15 pp. The hair canal (hc) above the sebaceous gland (sg) is narrow. C: At the stage 3 of hairless phenotype formation (day 15 pp) the dilation of HF infundibulum progresses downward and reaches the entrance of the sebaceous gland duct (sgd). The characteristic ampulliform structure is formed (as). D: hr/hr skin at day 15 pp (stage 2). The hair shaft (hs) loses its connection with the hair bulb and becomes loose. The IRS does not undergo normal shortening. The ORS portion just above the hair bulb narrows, and lacks its normal hair shaft content. E: hr/hr skin at day 15 pp (stages 3–5). The hair bulb shrinks abruptly. The HF portion between the DP and the proximal end of the hair shaft forms a narrow and curved strand of epithelial cells (es) which begins to disintegrate. The proximal part of the IRS coalesces around the end of the hair shaft. A rounded, abnormally large and bulbous club hair (ch) is formed. F: The IRS around the abnormal club hair (ch) prevents any possibility of direct contact with the ORS. G: The IRS abruptly disintegrates (stage 6) starting from its most proximal portion (white arrowhead) . Lacking any anchoring, the hair shaft starts to slip upward (bold arrow). H: Abnormal club hair is mechanically retained by a comb-like ORS structure in the zone of trichilemmal keratinization (tk). The dilation of the HF infundibulum (di) reaches its maximum. I: The shedding of the hair shaft results in formation of a utricle (u). The rest of the epithelial sheath disintegrates rapidly and only a small epithelial remnant (er) is visible close to the sebaceous gland (sg). J: The dermal papillae (dp) remain stranded in the deep dermis. The epithelial HF remnant (er) which contains the putative bulge derived cells is still associated with the arrector pili muscle (m). e, epidermis; sg, sebaceous gland; sgd, sebaceous gland duct; hs, hair shaft; dp, dermal papilla; ch, club hair; es, epithelial strand; irs, inner root sheath; ors, outer root sheath; tk, zone of trichilemmal keratinization; m, arrector pili muscle; uc, utricular cavity; er, epithelial HF remnants; sr, remnants of disintegrated epithelial strand. Scale bars: A-I, 23 μm; J, 50 μm. D and J, AP histochemistry; all others, H&E.

Figure 4.

Figure 4.

Alkaline phosphatase (A-D), IL-1R1 (E-I), and NCAM (J-M) reactivity in the skin of HRS/J hr/hr mice. A: In +/hr control skin at the middle catagen stage of HF regression (day 18 pp), the proximal IRS is significantly shortened, thus allowing direct contact between the ORS and the club hair (ch). The club hair has a serrated appearance, which provides the proper anchoring of the hair shaft in the epithelial mooring. B: hr/hr skin at day 15 pp (stage 3). The proximal part of the IRS coalesces around the end of the hair shaft. A rounded, abnormal club hair is formed. Dermal papilla (white arrowhead) is constantly AP-positive. C: The AP reactivity (black arrowhead) in the proximal ORS during initiation of hr/hr HF transformation (day 14 pp). Dermal papilla, white arrowhead. D: Dermal papilla remnants (dpr) remain stranded in the dermis after completion of HF disintegration and retain their strong AP-positivity. E: In the skin of heterozygous +/hr mice, strong IL-1R1 immunoreactivity was seen in the epithelial cells of the regressing ORS (es) throughout catagen phase (dermal papilla, white arrowhead). F: With progression of epithelial strand contraction in +/hr skin, the most intense Il-1R1 expression is seen in the portion of the epithelial strand (black arrowhead) directly adjacent to the distal pole of the dermal papilla (white arrowhead), which was always IL-1R1-negative. G: In the skin of homozygous hr/hr mice, the HF entry into hr transformation was associated with a prominent decline of IL-1R1 expression in the epithelial strand (es). The portion adjacent to the dermal papilla displays weak IL-1R1 positivity or negativity (black arrowhead). H: At stages 4 and 5 of hr/hr HF transformation, the keratinocytes of the epithelial strand located just above the dermal papilla become completely IL-1R1-negative (black arrowhead), while the dermal papilla (white arrowhead) retains the thin IL-1R1-positive epithelial sheath more prominently around its proximal pole. I: On days 19–20 of hr/hr HF transformation, when dermal papilla remnants turn into the amorphous ball-shaped structures, the associated IL-1R1 immunoreactivity lost its peripheral localization and was also seen inside these keratinocyte and fibroblast-containing cell clusters (white arrowhead). J: NCAM expression in the dermal papilla (white arrowhead) of hr/hr skin at day 14 pp (stage 1) is weak, while NCAM immunoreactivity in the perifollicular connective tissue sheath (cts) is prominent. K: In +/hr control skin during early catagen, NCAM immunoreactivity in the dermal papilla is more prominent compared to the corresponding stage of HF transformation in hr/hr skin (stage 1). L: At later stages of hr/hr HF transformation (stages 4–5), NCAM expression in the DP remains low, while in the connective tissue sheath (cts) it is very prominent. M: The dermal papilla remnants (dpr) stranded in the deep dermis after the completion of hairless phenotype formation are surrounded by an NCAM-positive connective tissue sheath. irse, inner root sheath end; cts, perifollicular connective tissue sheath; other legends same as Figure 3 ▶ . Scale bars: A-C, E-L, 23 μm; D and M, 50 μm.

Figure 5.

Figure 5.

TUNEL stain and Ki-67 immunoreactivity in hr/hr and +/hr HF. A: Premature and excessive apoptosis (apoptotic bodies in green color) in the hair matrix of hr/hr skin at day 15 pp (stage 1 of hr/hr HF transformation). Dermal papilla, white arrow. B: The apoptosis takes place in the same region of the hair matrix where the high level of proliferation is detected using Ki-67 immunostaining (red color) as a proliferation marker. C: In some cells, the TUNEL positivity colocalizes with Ki-67 expression (arrow). D: On day 15 pp, some TUNEL-positive DP cells are observed as well. E: In a minority of HF, massive apoptosis was seen in the DP (arrow). F: In +/hr control skin, the first TUNEL-positive cells in the proximal HF were detected at day 17 pp, after the prominent decrease of proliferative activity. This TUNEL-positivity was never as prominent as during the early stages of hr/hr HF transformation. G: Stages 4–5 of HF transformation in hr/hr skin. The DP is Ki-67- and TUNEL-negative. Some TUNEL-positive cells are present in the epithelial strand indicating the normal wave of intrafollicular apoptosis. H: There is no TUNEL positivity in the hair club region of hr/hr skin during HF disintegration. I: TUNEL-positive cells (arrow) in the hair club of +/hr HF in the corresponding stage of catagen transformation. J: At stage 6 of hr/hr HF transformation, the epithelial cells adjacent to the DP remnants start to proliferate. K: In the final stages (8–9) of hr/hr HF transformation, all epithelial cells that remain associated with the detached dermal papilla are proliferating, as confirmed by their active Ki-67 expression. Scale bars: A-H, 23 μm; I-J, 35 μm; K, 50 μm.

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