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The periderm is the outer layer of embryonic skin, which is essential for the development of the epidermis and the establishment of its barrier function. In humans, the periderm is a monolayer and is shed prenatally. The structure and fate of the mouse periderm remain puzzling. Using electron microscopy of mouse skin between the embryonic day 14.5 and the postnatal Day 2, we have assessed the periderm structure and its shedding patterns. In contrast to human periderm, the mouse periderm appears to be bilayered, comprising a presumably absorptive outer periderm with numerous microvilli and an inner periderm packed with specific (glycogen-containing?) granules. The desmosomes between the inner periderm and the underlying epidermis are scarce, and they are totally absent between the inner and the outer periderm. The inner and outer periderms in mice are shed at different stages of development: the outer periderm is shed in utero in conjunction with barrier acquisition (E16-18), while the inner periderm is retained postnatally. We assume that the bilayered structure of the mouse periderm and the postnatal retention of its inner layer represent the evolutionary adaptations in ancestral rodents which helps altricial newborns of their extant descendants to cope with acute dehydration right after birth and/or provides a substrate for proper bacterial colonization of newborn skin., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The secondary hair germ (SHG)-a transitory structure in the lower portion of the mouse telogen hair follicle (HF)-is directly involved in anagen induction and eventual HF regrowth. Some crucial aspects of SHG functioning and ontogenetic relations with other HF parts, however, remain undefined. According to recent evidence (in contrast to previous bulge-centric views), the SHG is the primary target of anagen-inducing signalling and a source of both the outer root sheath (ORS) and ascending HF layers during the initial (morphogenetic) anagen subphase. The SHG is comprised of two functionally distinct cell populations. Its lower portion (originating from lower HF cells that survived catagen) forms all ascending HF layers, while the upper SHG (formed by bulge-derived cells) builds up the ORS. The predetermination of SHG cells to a specific morphogenetic fate contradicts their attribution to the "stem cell" category and supports SHG designation as a "germinative" or a "founder" cell population. The mechanisms of this predetermination driving transition of the SHG from "refractory" to the "competent" state during the telogen remain unknown. Functionally, the SHG serves as a barrier, protecting the quiescent bulge stem cell niche from the extensive follicular papilla/SHG signalling milieu. The formation of the SHG is a prerequisite for efficient "precommitment" of these cells and provides for easier sensing and a faster response to anagen-inducing signals. In general, the formation of the SHG is an evolutionary adaptation, which allowed the ancestors of modern Muridae to acquire a specific, highly synchronized pattern of hair cycling., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is among the most toxic pollutants known to date that serves as a prototype for a group of halogenated hydrocarbon compounds characterized by extraordinary environmental persistence and unique ability to concentrate in animal and human tissues. TCDD can elicit a complex array of pleiotropic adverse effects in humans, although chloracne, a specific type of acne-like skin disease, is the only consistent manifestation of dioxin intoxication, thus representing a 'hallmark' of TCDD exposure. Chloracne is considered to be one of the most specific and sensitive biomarkers of TCDD intoxication that allows clinical and epidemiological evaluation of exposure level at threshold doses. The specific cellular and molecular mechanisms involved in pathogenesis of chloracne are still unknown. In this review, we summarize the available clinical data on chloracne and recent progress in understanding the role of the dioxin-dependent pathway in the control of gene transcription and discuss molecular and cellular events potentially involved in chloracne pathogenesis. We propose that the dioxin-induced activation of skin stem cells and a shift in differentiation commitment of their progeny may represent a major mechanism of chloracne development.

Ribozyme technology is widely used to target mRNA in a sequence-specific fashion and thus change the expression pattern of cells or tissues. While the goal of mRNA targeting is usually the cleavage of mutant mRNAs with the prospect of gene therapy for inherited diseases, in certain instances, targeting of wild-type genes can be used therapeutically. Lack of expression of the mouse hairless gene due to inherited mutations leads to the complete and irreversible loss of hair known as atrichia. We designed this study to recapitulate the hairless phenotype in a restricted manner by topical application of deoxyribozyme-targeting molecules to specifically cleave the mouse hairless mRNA. Histological samples taken from treated skin at different times demonstrated a decreased number of hair follicles, an involution of the remaining follicles, a separation of the dermal papillae, and the presence of dermal cysts, all characteristics of the hairless phenotype, but not normally present in the skin of C57Bl/6 J mice. In this study, we successfully recapitulated the hairless phenotype using topically applied target-specific catalytic oligonucleotides designed to cleave the mouse hairless mRNA. Our results demonstrate the feasibility of using ribozyme technology to alter the gene expression in the skin via topical application and provide proof of principle for the development of this strategy for permanent hair removal.

Desmocollins, members of the desmosomal cadherin family, are known to play an important role in desmosomal intercellular adhesion. The human desmosomal cadherin cluster is located on chromosome 18q12, and consists of three desmoglein and three desmocollin genes. The cDNAs of all six of these genes have been cloned and sequenced, however, the exon-intron organization was reported for only one human desmocollin gene, DSC2. We elucidated the exon-intron structures of the DSC1 and DSC3 genes using PCR amplification of genomic DNA and direct sequencing of BAC clones. The results suggest a strong evolutionary conservation between the genomic organization of the desmocollin genes.

The human desmoglein genes, desmogleins 1--3, are members of the desmosomal cadherin superfamily, and encode critical components of the desmosome. These genes are tightly clustered within 150--200 kb of chromosome 18q12.1 and represent excellent candidate genes for genetic disorders of the epidermis linked to this region of the genome. Mutations in desmoglein 1 have already been implicated in the genetic disorder striate palmoplantar keratoderma. Similarly, a mutation in desmoglein 3 underlies the balding mouse phenotype, although no human mutations in desmoglein 3 have been identified to date. In this study, we have characterized the genomic organization of two of the three desmoglein genes mapped to chromosome 18q12. Comparison of their exon-intron structure reveals the high level of evolutionary conservation expected from these related genes. The identification of the genomic structure of the desmoglein genes will facilitate mutation detection in genodermatoses with desmosomal abnormalities resulting from underlying defects in these genes.

The hair follicle is characterized by cyclic transformations from active growth and hair fiber production through regression into a resting phase. The growth phase, known as anagen, is associated with rapid rates of cell turnover, and variations in the rate of DNA synthesis in mouse skin throughout the hair cycle are accompanied by changes in the activity of ornithine decarboxylase (ODC), a key enzyme in the synthesis of polyamines, which are actively involved in regulation of normal cell division, differentiation, and growth. Previously, a transgenic mouse was created that overexpressed ODC in the skin using a K6 promoter. The first hair cycle in neonatal transgenic mice appeared to be normal, but by the third week of postnatal life transgenic pups begin to progressively lose hair. The lower portion of the hair follicle was progressively replaced with enlarging cystic structures located in the deep dermis, and the transgenic mice exhibited excessive growth of skin mass resulting in pronounced wrinkling and folding. Interestingly, these findings bore striking resemblance to the rhino mouse phenotype and to human patients with papular atrichia, a rare congenital ectodermal disorder characterized by progressive and irreversible hair loss in early childhood. The similarities in phenotype between transgenic mice and human atrichia with papular lesions suggest that ODC transgenics may represent a useful model for studying this disorder. It appears that ODC plays a functionally important, yet still obscure role in a complex metabolic pathway that is critical in hair follicle function not only in mice, but in humans as well.

Congenital atrichia with papular lesions is a rare, recessively inherited form of hair loss characterized by a complete absence of all body hair shortly after birth. Mutations in the human ortholog of the mouse hairless (hr) gene have been implicated in the pathogenesis of this disorder. In this study, we screened, by direct sequence analysis, the hairless gene in a family of Polish descent and identified a novel missense mutation (C622G). The mutation alters the third of four invariant cysteins in the zinc-finger domain, which has high homology to the C-X-X-C-(X)17-C-X-X-C structure of the zinc-fingers of the GATA family of transcription factors. The human hairless gene encodes a putative transcription factor with restricted expression in the brain and skin, which is involved in the regulation of apoptosis during catagen remodeling in the hair cycle.

In 1989, mice bearing mutations at the hr (hairless) locus were first proposed as a model for the human hair growth disorder papular atrichia, since in both these mice and in corresponding patients, a complete hair loss develops due to disintegration of the normal follicle structure into dermal cysts and so-called utriculi. Recently, the human hairless gene was characterized, and pathogenetic mutations were found to be associated with a recessively inherited form atrichia with papular lesions; however, the functions of hr gene remain unclear. Allelic mutations in the murine hairless gene represent a potentially powerful tool to elucidate the role of the hairless gene protein product in hair follicle physiology. In 1980, several naked animals were discovered in a breeding colony of B10.R109/Y mice maintained in the Laboratory of Experimental Biological Models (L.E.B.M., Yurlovo, Moscow District, Russia). By cross breeding with hairless HRS/J hr/hr mice, this mutation was shown to be allelic with hairless. Here, we describe the molecular basis of the hr(rhY) mutation in mice, which consists of a 13 bp insertion in exon 16 of the hr gene. Histological evaluation of Yurlovo mouse skin revealed some differences as compared to the hairless and rhino mutations, with the formation of dermal megacysts being the most specific peculiarity of the Yurlovo mutation. These results, together with previous studies of hr(rhY)/hr(rhY) mutant mice, suggest that the rhino Yurlovo (hr(rhY)) mutation represents a third and potentially more severe variation of the hairless phenotype.

The hairless and rhino mutations are autosomal recessive allelic mutations that map to mouse Chromosome 14. In general, the rhino phenotype is a more severe manifestation of the hairless phenotype. In both hairless and rhino mice, the hair begins shedding in a cephalocaudal pattern within 7 days after birth, and never regrows due to a series of irreversible cellular events. The hairless mutation closely resembles the human disease known as papular atrichia (MIM 209500). Recently, this disease was linked to Chromosome 8p12, the human homolog of hairless was cloned and mapped to the same locus, and mutations have been identified in several different families. In order to gain insight into the pathophysiology of disease in papular atrichia, we sought to utilize mouse mutations as in vivo model systems. In this study, we report the identification of a homozygous nonsense mutation in the coding region of the hr gene in a hairless mouse captured on a chicken farm in the Midwestern United States. To reflect the place of identification of this new mutation at the hr locus, we have designated this allele hr(rhChr) using the laboratory code Chr (Christiano).

For many years, hairless and rhino mouse mutants have provided a useful and extensively exploited model for studying different aspects of skin physiology, including skin aging, pharmacokinetic evaluation of drug activity and cutaneous absorption, skin carcinogenesis, and skin toxicology. Interestingly, however, hairless and rhino mice have rarely been studied for their primary cellular defect - hairlessness - and thus, the hairless gene itself and its physiological functions have been largely overlooked for decades. The recent identification of the human homolog of the hairless gene on human Chromosome 8p12 confirmed the clinical significance of the phenomenon of "hairlessness" in humans, which was predicted on the basis of similarities between hairless mice and a congenital hair disorder characterized by atrichia with papules. Mutations in the hairless gene of mice provide instructive models for further studies of hr gene function, and may facilitate insights into the pathophysiology of different human disorders associated with the disruption of hr gene activity. We provide an overview of current data on the structure and expression patterns of the hr gene, and of mutations at the hairless locus in mice and humans, including the genetic basis of different alleles, the pathology of hairlessness, reproductive and immunological defects, and susceptibility to dioxin toxicity. On the basis of our current understanding of hairlessness, we speculate on the putative functions of the hr gene product in skin physiology, and particularly, in hair follicle biology.