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Naked mole-rats (NMRs) (Heterocephalus glaber) are long-lived mammals that possess a natural resistance to cancer and other age-related pathologies, maintaining a healthy life span >30 years. In this study, using immunohistochemical and RNA-sequencing analyses, we compare skin morphology, cellular composition, and global transcriptome signatures between young and aged (aged 3‒4 vs. 19‒23 years, respectively) NMRs. We show that similar to aging in human skin, aging in NMRs is accompanied by a decrease in epidermal thickness; keratinocyte proliferation; and a decline in the number of Merkel cells, T cells, antigen-presenting cells, and melanocytes. Similar to that in human skin aging, expression levels of dermal collagens are decreased, whereas matrix metalloproteinase 9 and matrix metalloproteinase 11 levels increased in aged versus in young NMR skin. RNA-sequencing analyses reveal that in contrast to human or mouse skin aging, the transcript levels of several longevity-associated (Igfbp3, Igf2bp3, Ing2) and tumor-suppressor (Btg2, Cdkn1a, Cdkn2c, Dnmt3a, Hic1, Socs3, Sfrp1, Sfrp5, Thbs1, Tsc1, Zfp36) genes are increased in aged NMR skin. Overall, these data suggest that specific features in the NMR skin aging transcriptome might contribute to the resistance of NMRs to spontaneous skin carcinogenesis and provide a platform for further investigations of NMRs as a model organism for studying the biology and disease resistance of human skin., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Histone deacetylases (HDACs) induce gene repression and modify the activity of nonhistone proteins. In a new article in the Journal of Investigative Dermatology, Zhu et al. (2021) demonstrate essential roles for HDAC1/2 in maintaining keratinocyte proliferation and survival in adult epidermis and basal cell carcinoma, thus providing a rationale for using HDAC inhibitors for the treatment of hyperproliferative and neoplastic skin disorders., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

The maintenance of a proper nuclear architecture and three-dimensional organization of the genes, enhancer elements, and transcription machinery plays an essential role in tissue development and regeneration. Here we show that in the developing skin, epidermal progenitor cells of mice lacking p63 transcription factor display alterations in the nuclear shape accompanied by a marked decrease in expression of several nuclear envelope-associated components (Lamin B1, Lamin A/C, Sun1, Nesprin-3, Plectin) compared with controls. Furthermore, chromatin immunoprecipitation-quantitative PCR assay showed enrichment of p63 on Sun1, Syne3, and Plec promoters, suggesting them as p63 targets. Alterations in the nuclei shape and expression of nuclear envelope-associated proteins were accompanied by altered distribution patterns of the repressive histone marks trimethylation on lysine 27 of histone H3, trimethylation on lysine 9 of histone H3, and heterochromatin protein 1-alpha in p63-null keratinocytes. These changes were also accompanied by downregulation of the transcriptional activity and relocation of the keratinocyte-specific gene loci away from the sites of active transcription toward the heterochromatin-enriched repressive nuclear compartments in p63-null cells. These data demonstrate functional links between the nuclear envelope organization, chromatin architecture, and gene expression in keratinocytes and suggest nuclear envelope-associated genes as important targets mediating p63-regulated gene expression program in the epidermis., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Three-dimensional organization of transcription in the nucleus and mechanisms controlling the global chromatin folding, including spatial interactions between the genes, noncoding genome elements, and epigenetic and transcription machinery, are essential for establishing lineage-specific gene expression programs during cell differentiation. Spatial chromatin interactions in the nucleus involving gene promoters and distal regulatory elements are currently considered major forces that drive cell differentiation and genome evolution in general, and such interactions are substantially reorganized during many pathological conditions. During terminal differentiation of the epidermal keratinocytes, the nucleus undergoes programmed transformation from highly active status, associated with execution of the genetic program of epidermal barrier formation, to a fully inactive condition and finally becomes a part of the keratinized cells of the cornified epidermal layer. This transition is accompanied by marked remodeling of the three-dimensional nuclear organization and microanatomy, including changes in the spatial arrangement of lineage-specific genes, nuclear bodies, and heterochromatin. This mini-review highlights the important landmarks in the accumulation of our current knowledge on three-dimensional organization of the nucleus, spatial arrangement of the genes, and their distal regulatory elements, and it provides an update on the mechanisms that control higher-order chromatin remodeling in the context of epidermal keratinocyte differentiation in the skin., (Copyright © 2016 The Author. Published by Elsevier Inc. All rights reserved.)

The Polycomb group proteins are transcriptional repressors that are critically important in the control of stem cell activity and maintenance of the identity of differentiated cells. Polycomb proteins interact with each other to form chromatin-associated repressive complexes (Polycomb repressive complexes 1 and 2) leading to chromatin compaction and gene silencing. However, the roles of the distinct components of the Polycomb repressive complex 2 in the control of skin development and keratinocyte differentiation remain obscure. Dauber et al. demonstrate the conditional ablations of three essential Polycomb repressive complex 2 subunits (EED, Suz12, or Ezh1/2) in the epidermal progenitors result in quite similar skin phenotypes including premature acquisition of a functional epidermal barrier, formation of ectopic Merkel cells, and defective postnatal hair follicle development. The reported data demonstrate that in skin epithelia, EED, Suz12, and Ezh1/2 function largely as subunits of the Polycomb repressive complex 2, which is important in the context of data demonstrating their independent activities in other cell types. The report provides an important platform for further analyses of the role of distinct Polycomb components in the control of gene expression programs in the disorders of epidermal differentiation, such as psoriasis and epidermal cancer., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Chemotherapy-induced hair loss is one of the most devastating side effects of cancer treatment. To study the effects of chemotherapeutic agents on the hair follicle, a number of experimental models have been proposed. Yoon et al. report that transplantation of human scalp hair follicles onto chemotherapy-treated immunodeficient mice serves as an excellent in vivo model for chemotherapy-induced hair loss. Yoon et al. demonstrate that (i) the response of human hair follicles grafted onto immunodeficient mice to cyclophosphamide resembles the key features of the chemotherapy-induced hair loss seen in patients with cancer and (ii) this human in vivo model for chemotherapy-induced hair loss is closer to clinical reality than to any earlier models. Undoubtedly, this model will serve as a valuable tool for analyses of the mechanisms that underlie this devastating side effect of anti-cancer therapy., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Chemotherapy has severe side effects in normal rapidly proliferating organs, such as hair follicles, and causes massive apoptosis in hair matrix keratinocytes followed by hair loss. To define the molecular signature of hair follicle response to chemotherapy, human scalp hair follicles cultured ex vivo were treated with doxorubicin (DXR), and global microarray analysis was performed 3 hours after treatment. Microarray data revealed changes in expression of 504 genes in DXR-treated hair follicles versus controls. Among these genes, upregulations of several tumor necrosis factor family of apoptotic receptors (FAS, TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) receptors 1/2), as well as of a large number of keratin-associated protein genes, were seen after DXR treatment. Hair follicle apoptosis induced by DXR was significantly inhibited by either TRAIL-neutralizing antibody or caspase-8 inhibitor, thus suggesting a previously unreported role for TRAIL receptor signaling in mediating DXR-induced hair loss. These data demonstrate that the early phase of the hair follicle response to DXR includes upregulation of apoptosis-associated markers, as well as substantial reorganization of the terminal differentiation programs in hair follicle keratinocytes. These data provide an important platform for further studies toward the design of effective approaches for the management of chemotherapy-induced hair loss.

The nucleus of epidermal keratinocytes (KCs) is a complex and highly compartmentalized organelle, whose structure is markedly changed during terminal differentiation and transition of the genome from a transcriptionally active state seen in the basal and spinous epidermal cells to a fully inactive state in the keratinized cells of the cornified layer. Here, using multicolor confocal microscopy, followed by computational image analysis and mathematical modeling, we demonstrate that in normal mouse footpad epidermis, transition of KCs from basal epidermal layer to the granular layer is accompanied by marked differences in nuclear architecture and microenvironment including the following: (i) decrease in the nuclear volume; (ii) decrease in expression of the markers of transcriptionally active chromatin; (iii) internalization and decrease in the number of nucleoli; (iv) increase in the number of pericentromeric heterochromatic clusters; and (v) increase in the frequency of associations between the pericentromeric clusters, chromosomal territory 3, and nucleoli. These data suggest a role for nucleoli and pericentromeric heterochromatin clusters as organizers of nuclear microenvironment required for proper execution of gene expression programs in differentiating KCs, and provide important background information for further analyses of alterations in the topological genome organization seen in pathological skin conditions, including disorders of epidermal differentiation and epidermal tumors.

The nucleus is a complex and highly compartmentalized organelle, which undergoes major organization changes during cell differentiation, allowing cells to become specialized and fulfill their functions. During terminal differentiation of the epidermal keratinocytes, the nucleus undergoes a programmed transformation from active status, associated with execution of the genetic programs of cornification and epidermal barrier formation, to a fully inactive condition and becomes a part of the keratinized cells of the cornified layer. Tremendous progress achieved within the past two decades in understanding the biology of the nucleus and epigenetic mechanisms controlling gene expression allowed defining several levels in the regulation of cell differentiation-associated gene expression programs, including an accessibility of the gene regulatory regions to DNA-protein interactions, covalent DNA and histone modifications, and ATP-dependent chromatin remodeling, as well as higher-order chromatin remodeling and nuclear compartmentalization of the genes and transcription machinery. Here, we integrate our current knowledge of the mechanisms controlling gene expression during terminal keratinocyte differentiation with distinct levels of chromatin organization and remodeling. We also propose directions to further explore the role of epigenetic mechanisms and their interactions with other regulatory systems in the control of keratinocyte differentiation in normal and diseased skin.

Neuroimmune dysregulation characterizes atopic disease, but its nature and clinical impact remain ill-defined. Induced by stress, the neurotrophin nerve growth factor (NGF) may worsen cutaneous inflammation. We therefore studied the role of NGF in the cutaneous stress response in a mouse model for atopic dermatitis-like allergic dermatitis (AlD). Combining several methods, we found that stress increased cutaneous but not serum or hypothalamic NGF in telogen mice. Microarray analysis showed increased mRNAs of inflammatory and growth factors associated with NGF in the skin. In stress-worsened AlD, NGF-neutralizing antibodies markedly reduced epidermal thickening together with NGF, neurotrophin receptor (tyrosine kinase A and p75 neurotrophin receptor), and transforming growth factor-β expression by keratinocytes but did not alter transepidermal water loss. Moreover, NGF expression by mast cells was reduced; this corresponded to reduced cutaneous tumor necrosis factor-α (TNF-α) mRNA levels but not to changes in mast cell degranulation or in the T helper type 1 (Th1)/Th2 cytokine balance. Also, eosinophils expressed TNF receptor type 2, and we observed reduced eosinophil infiltration after treatment with NGF-neutralizing antibodies. We thus conclude that NGF acts as a local stress mediator in perceived stress and allergy and that increased NGF message contributes to worsening of cutaneous inflammation mainly by enhancing epidermal hyperplasia, pro-allergic cytokine induction, and allergy-characteristic cellular infiltration.

BMP signaling has a crucial role in skin development and homeostasis, whereas molecular mechanisms underlying its involvement in regulating gene expression programs in keratinocytes and fibroblasts remain largely unknown. We show here that several BMP ligands, all BMP receptors, and BMP-associated Smad1/5/8 are expressed in human primary epidermal keratinocytes and dermal fibroblasts. Treatment of both cell types by BMP-4 resulted in the activation of the BMP-Smad, but not BMP-MAPK pathways. Global microarray analysis revealed that BMP-4 treatment induces distinct and cell type-specific changes in gene expression programs in keratinocytes and fibroblasts, which are far more complex than the effects of BMPs on cell proliferation/differentiation described earlier. Furthermore, our data suggest that the potential modulation of cell adhesion, extracellular matrix remodeling, motility, metabolism, signaling, and transcription by BMP-4 in keratinocytes and fibroblasts is likely to be achieved by the distinct and cell-type-specific sets of molecules. Thus, these data provide an important basis for delineating mechanisms that underlie the distinct effects of the BMP pathway on different cell populations in the skin, and will be helpful in further establishing molecular signaling networks regulating skin homeostasis in health and disease.

Alopecia areata (AA) is an autoimmune disorder of the hair follicle characterized by inflammatory cell infiltrates around actively growing (anagen) hair follicles. Substance P (SP) plays a critical role in the cutaneous neuroimmune network and influences immune cell functions through the neurokinin-1 receptor (NK-1R). To better understand the role of SP as an immunomodulatory neuropeptide in AA, we studied its expression and effects on immune cells in a C3H/HeJ mouse model for AA. During early stages of AA development, the number of SP-immunoreactive nerve fibers in skin is increased, compared to non-affected mice. However, during advanced stages of AA, the number of SP-immunoreactive nerves and SP protein levels in skin are decreased, whereas the expression of the SP-degrading enzyme neutral endopeptidase (NEP) is increased, compared to control skin. In AA, NK-1R is expressed on CD8+ lymphocytes and macrophages accumulating around affected hair follicles. Additional SP supply to the skin of AA-affected mice leads to a significant increase of mast cell degranulation and to accelerated hair follicle regression (catagen), accompanied by an increase of CD8+ cells-expressing granzyme B. These data suggest that SP, NEP, and NK-1R serve as important regulators in the molecular signaling network modulating inflammatory response in autoimmune hair loss.

Neurotrophins (NTs) belong to a family of growth factors, which control the development, maintenance, and apoptotic death of neurons and also fulfill multiple regulatory functions outside the nervous system. Biological effects induced by NTs strongly depend on the pattern of NT receptor/co-receptors expression in target cells, as well as on the set of intracellular adaptor molecules that link NT signalling to distinct biochemical pathways. In this review, we summarize data on the molecular mechanisms underlying the involvement of NTs in the control of non-neuronal functions in normal skin (e.g. keratinocyte proliferation, melanocyte development and apoptosis, hair growth). We also review the data on the role for NTs and their receptors in a number of pathological skin conditions (stress-induced hair loss, psoriasis, atopic dermatitis). Although additional efforts are required to fully understand mechanisms underlying the involvement of NTs and their receptors in controlling functions of normal and pathologically altered skin cells, substantial evidence suggests that modulation of NT signalling by NTs receptor agonists/antagonists may be developed as intervention modalities in distinct skin and hair growth pathologies.

Melanin synthesis in the hair follicle (HF) is strictly coupled to the growth stage of the hair cycle and is interrupted during follicle regression (catagen) and resting. Using tyrosine-related protein 2 (Trp)2-LacZ transgenic mice as a model, we show that distinct melanocyte subpopulations of the HF display distinct patterns of apoptosis and survival during catagen. Melanocytes located in the outer root sheath express Bcl-2 and are TUNEL-negative. Part of the pigment-producing melanocytes located above the follicular papilla expresses Fas, TUNEL, and is likely to undergo apoptosis, whereas the other part of these melanocytes expresses c-kit, Bcl-2, and becomes visible in the follicular papilla. During late catagen, TUNEL and Ki-67 negative melanocytes expressing Bcl-2 are seen in the secondary germ of the HF. Lack of proliferation in the follicular melanocytes during catagen suggests that secondary hair germ of late catagen HF is most likely repopulated by melanocytes arising from the outer root sheath or follicular papilla of early/mid-catagen HF. Taken together, these data suggest a possible scenario and mechanisms of the remodeling of the follicular pigmentary unit during HF anagen-catagen-telogen transition and may be used for the establishing in vivo models for pharmacological modulation of melanocyte apoptosis and survival during the hair cycle.

In mammalian skin, stem cell factor (SCF) regulates the proliferation and maturation of mast cells and melanocytes, which are thought to be the only cutaneous cells that express the Kit-tyrosine kinase receptor (Kit) and respond to epithelial and mesenchymal-derived SCF. We previously had noted, however, the presence of Kit+ cells in murine hair follicles, in an introepithelial tissue compartment devoid of melanocytes and mast cells. Here we have identified the nature of this Kit+ population of cells in hair follicles of C57BL/6 mice. Anagen hair follicles showed strong Kit immunoreactivity not only in the pigmentary unit above the follicular dermal papilla but also in a much more proximally located, homogenous group of nondendritic, nonmelanized cells. By immunohistochemistry (desmoplakin+/Trp-1-) and electron microscopy (presence of tonofilaments, desmosomes, lack of melanosomes), these Kit+ cells were shown to be hair matrix keratinocytes and were also found in melanocyte-deficient hair follicles (Kit(Sl)/Kit(Sl-d) mice, Kit-neutralizing antibody-treated C57BL/6 mice). Expression of Kit and SCF was strongly hair-cycle-dependent, suggesting a functional role of epithelial Kit expression in hair growth control. This was supported by the observation that mice unable to respond to SCF stimulation (Kit(W)/Kit(W-v)) showed a significant retardation of anagen development compared to their wild-type littermates. The expression of Kit in the most rapidly proliferating compartment of the hair follicle epithelium suggests intriguing, as yet unexplored new functions of Kit signaling in epithelial cell biology.

Bone morphogenetic proteins (BMP) are members of the transforming growth factor-beta superfamily regulating a large variety of biologic responses in many different cells and tissues during embryonic development and postnatal life. BMP exert their biologic effects via binding to two types of serine/threonine kinase BMP receptors, activation of which leads to phosphorylation and translocation into the nucleus of intracellular signaling molecules, including Smad1, Smad5, and Smad8 ("canonical" BMP signaling pathway). BMP effects are also mediated by activation of the mitogen-activated protein (MAP) kinase pathway ("noncanonical" BMP Signaling pathway). BMP activity is regulated by diffusible BMP antagonists that prevent BMP interactions with BMP receptors thus modulating BMP effects in tissues. During skin development, BMPs its receptors and antagonists show stringent spatiotemporal expressions patterns to achieve proper regulation of cell proliferation and differentiation in the epidermis and in the hair follicle. In normal postnatal skin, BMP are involved in the control of epidermal homeostasis, hair follicle growth, and melanogenesis. Furthermore, BMP are implicated in a variety of pathobiologic processes in skin, including wound healing, psoriasis, and carcinogenesis. Therefore, BMPs represent new important players in the molecular network regulating homeostasis in normal and diseased skin. Pharmacologic modulation of BMP signaling may be used as a new approach for managing skin and hair disorders.

Chemotherapy alters the structure and function of hair follicle melanocytes. Molecular mechanisms controlling melanocyte responses during chemotherapy-induced hair loss, however, remain largely unknown. Using immunohistology and multicolor confocal microscopy, we show here that cyclophosphamide administration to C57BL/6 mice alters the activity and fate of hair follicle melanocytes. After 24-48 h, hair bulb melanocytes expressing Fas undergo apoptosis. The number of apoptotic follicular melanocytes is significantly reduced (p<0.01) in cyclophosphamide-treated Fas knockout mice compared to wild-type controls, suggesting that Fas signaling contributes to chemotherapy-induced melanocyte death. After 3-5 d, surviving hair bulb melanocytes express c-kit receptor, proliferate, and appear to migrate up the outer root sheath. Tyrosinase-positive and melanogenically active cells then appear in the epidermis. By Western blotting and immunohistochemistry, expression levels of the c-kit ligand, stem cell factor, in skin and epidermis are strongly increased after cyclophosphamide treatment. Cyclophosphamide-induced migration of the hair follicle melanocytes into epidermis is completely abrogated by administration of c-kit neutralizing antibody. These data suggest that chemotherapy induces a complex response in the hair follicle melanocytes, which includes apoptosis, proliferation, and migration. Pharmacologic manipulation of Fas and c-kit signaling pathways might be useful for the correction of skin hyperpigmentation as a side-effect of chemotherapy.

Increasing evidence suggests that morphogenesis of the distinct developmental structures derived from the same organ-committed epithelium is controlled by differential mechanisms. As was recently shown in mice with mutations in the downless (dL) gene, induction of primary or tylotrich hair follicles is strikingly dependent of signaling through the Tnf receptor homologue, Edar. Here, we show that dorsal skin of murine embryos with constitutive deletion of the BMP2/4 antagonist noggin, after transplantation into SCID mice, is characterized by the lack of induction of secondary hair follicles, and by the arrest of primary hair follicle development prior to hair shaft formation. The loss of noggin activity was associated with failure to express genes that specify hair follicle cell fates in the epidermis (Lef-1, beta-catenin, Shh) and dermal papilla (p75 kDa neurotrophin receptor, alkaline phosphatase). This suggests that regulation of BMP2/4 signaling by noggin is essential for the induction of secondary hair follicles, as well as for advanced stages of development in primary hair follicles.

As the neuropeptide substance P can manipulate murine hair growth in vivo, we here further studied the role of sensory neuropeptides in hair follicle biology by determining the distribution and hair-cycle-dependent remodeling of the sensory innervation in C57BL/6 mouse back skin. Calcitonin-gene-related peptide, substance P, and peptide histidine methionine (employed as vasoactive intestinal peptide marker) were identified by immunohistochemistry. All of these markers immunolocalized to bundles of nerve fibers and to single nerve fibers, with distinct distribution patterns and major hair-cycle-associated changes. In the epidermis and around the distal hair follicle and the arrector pili muscle, only calcitonin-gene-related peptide immunoreactive nerve fibers were visualized, whereas substance P and peptide histidine methionine immunoreactive nerve fibers were largely restricted to the dermis and subcutis. Compared to telogen skin, the number of calcitonin-gene-related peptide, substance P, and peptide histidine methionine immunoreactive single nerve fibers increased significantly (p < 0.01) during anagen, including around the bulge region (the seat of epithelial stem cells). Substance P significantly accelerated anagen progression in murine skin organ culture, whereas calcitonin-gene-related peptide and a substance-P-inhibitory peptide inhibited anagen (p < 0.05). The inhibitory effect of calcitonin-gene-related peptide could be antagonized by coadministrating substance P. In contrast to substance P, calcitonin-gene-related peptide failed to induce anagen when released from subcutaneous implants. This might reflect a differential functional assignment of the neuropeptides calcitonin-gene-related peptide and substance P in hair growth control, and invites the use of neuropeptide receptor agonists and antagonists as novel pharmacologic tools for therapeutic hair growth manipulation.

Increasing evidence suggests that neurotrophins play an important part in the control of the development of ectodermal derivatives, such as the hair follicle. Here, we show that, during hair follicle morphogenesis in C57BL/6 mice, nerve growth factor, brain-derived neurotrophic factor and their corresponding high-affinity tyrosine kinase receptors, TrkA and TrkB, show stringently controlled spatiotemporal expression patterns in the follicular epithelium and mesenchyme. Constitutive overexpression of nerve growth factor in mice is associated with a discrete, but significant acceleration of hair follicle morphogenesis, whereas this is not seen in brain-derived neurotrophic factor transgenic mice. In neonatal skin organ culture, nerve growth factor and brain-derived neurotrophic factor differentially influence hair follicle development: nerve growth factor accelerates late stages of hair follicle morphogenesis, whereas brain-derived neurotrophic factor does not show significant effects. This suggests that the morphogenetic properties of locally generated neurotrophins in the skin, similar to their classical neurotrophic functions, are quite distinct and depend on the response patterns of the corresponding neurotrophin target receptor-expressing cells in the developing hair follicle. These data further strengthen the concept that neurotrophin signaling is an important element in controlling the rate of hair follicle morphogenesis, yet also highlight the complexity of this signaling system.

Skin nerves may exert "trophic" functions during hair follicle development, growth, and/or cycling. Here, we demonstrate hair cycle-related plasticity in the sympathetic innervation of skin and hair follicle in C57BL/6 mice. Compared with telogen skin, the number of nerve fibers containing norepinephrine or immunoreactive for tyrosine hydroxylase increased during the early growth phase of the hair cycle (anagen) in dermis and subcutis. The number of these fibers declined again during late anagen. beta2-adrenoreceptor-positive keratinocytes were transiently detectable in the noncycling hair follicle epithelium, especially in the isthmus and bulge region, but only during early anagen. In early anagen skin organ culture, the beta2-adrenoreceptor agonist isoproterenol promoted hair cycle progression from anagen III to anagen IV. The observed hair cycle-dependent changes in adrenergic skin innervation on the one hand, and hair growth modulation by isoproterenol, accompanied by changes in beta2-adrenoreceptor expression of selected regions of the hair follicle epithelium on the other, further support the concept that bi-directional interactions between the hair follicle and its innervation play a part in hair growth control. This invites one to systematically explore the neuropharmacologic manipulation of follicular neuroepithelial interactions as a novel therapeutic strategy for managing hair growth disorders.

The fate of the hair follicle pigmentary unit during the cyclical involution of anagen hair follicles is unknown. Using the C57BL/6 mouse model for hair research, hair follicle melanocytes were examined during the anagen-catagen transformation, comparing spontaneous and pharmacologically induced catagen development. This study shows that both spontaneous catagen and dexamethasone-induced catagen display similar changes in the pigmentary unit. Catagen hair follicles exhibited pigment incontinence in the dermal papilla and in selected outer root sheath keratinocytes. Melanocytes deleted by apoptosis were detected in spontaneous catagen and, more commonly, in dexamethasone-induced catagen, and were identified using transmission electron microscopy by the presence of free premelanosomes in affected cells lacking epithelial specializations, and by the colocalization of TUNEL positivity and tyrosinase-related protein-1 immunoreactivity. By contrast, cyclophosphamide-induced catagen was characterized by the initial retention of melanogenic and dendritic melanocytes in the presence of widespread keratinocyte apoptosis. Melanocyte incontinence and the ectopic distribution of melanin were more severe than in the other forms of catagen. Whereas much of this melanin was extruded, via the hair canal, to the skin surface, hair follicle-derived pigment was also detected within the epidermis, probably derived from pigment-carrying migrating outer root sheath keratinocytes from the proximal hair follicle. Thus, apoptosis may account, at least in part, for the loss of melanogenic melanocytes during spontaneous catagen. Although dexamethasone-induced catagen may provide a useful model for general hair pigmentation research, catagen induced by cyclophosphamide offers an interesting model for studying the response, and relative resistance, of melanocytes to chemical injury.

Hair follicle epithelium and nervous system share a common ectodermal origin, and some neurotrophins can modulate keratinocyte proliferation and apoptosis. It is therefore reasonable to ask whether growth factors that control neural development are also involved in the regulation of hair follicle morphogenesis. Focusing on neurotrophin-3 (NT-3) and its high-affinity-receptor [tyrosine kinase C (TrkC)], we show that hair placode keratinocytes express TrkC mRNA and immunoreactivity early during murine hair follicle morphogenesis. In later stages of hair follicle development, TrkC mRNA, TrkC-, and NT-3-immunoreactivity are seen in keratinocytes of the proximal hair bulb as well as in dermal papilla fibroblasts. Compared with the corresponding wild-type animals, early stages of hair follicle morphogenesis are significantly accelerated in newborn NT-3 overexpressing mice, whereas these are retarded in newborn heterozygous NT-3 knockout (+/-) mice. These observations suggest that NT-3 is an important growth modulator during morphogenesis and remodeling of neuroectodermal-mesenchymal interaction systems like the hair follicle.