Mammalian-specific ectodermal enhancers control the expression of Hoxc genes in developing nails and hair follicles.

Vertebrate Hox genes are critical for the establishment of structures during the development of the main body axis. Subsequently, they play important roles either in organizing secondary axial structures such as the appendages, or during homeostasis in postnatal stages and adulthood. Here, we set up to analyze their elusive function in the ectodermal compartment, using the mouse limb bud as a model. We report that the HoxC gene cluster was co-opted to be transcribed in the distal limb ectoderm, where it is activated following the rule of temporal colinearity. These ectodermal cells subsequently produce various keratinized organs such as nails or claws. Accordingly, deletion of the HoxC cluster led to mice lacking nails (anonychia), a condition stronger than the previously reported loss of function of Hoxc13, which is the causative gene of the ectodermal dysplasia 9 (ECTD9) in human patients. We further identified two mammalian-specific ectodermal enhancers located upstream of the HoxC gene cluster, which together regulate Hoxc gene expression in the hair and nail ectodermal organs. Deletion of these regulatory elements alone or in combination revealed a strong quantitative component in the regulation of Hoxc genes in the ectoderm, suggesting that these two enhancers may have evolved along with the mammalian taxon to provide the level of HOXC proteins necessary for the full development of hair and nail.

The concept of the onychodermis (specialized nail mesenchyme): an embryological assessment and a comparative analysis with the hair follicle.

BACKGROUND: Recently, an intriguing concept was introduced into the literature that defines the area underlying the nail bed as a specific mesenchymal substructure unique to the nail organ. It has been termed onychodermis. The onychodermis expresses CD10 with remarkable specificity. Herein, we compare adult and fetal human hair follicles with fetal nail organs in an attempt to draw analogies for the mesenchyme associated with both adnexal structures. METHODS: We examined immunohistochemically samples from adult and fetal hair follicles for the expression of CD10, CD34 and the mesenchymal stem cell marker nestin and compared the antigen profile with that of the fetal nail organ. RESULTS: The CD10-positive/CD34-negative onychodermis is prominently visible at the end of the second trimester. A corresponding follicular structure was not identified, either in the adult or in the developing hair follicle. Nestin staining does not define the onychodermis. CONCLUSIONS: The concept of the onychodermis is equally valid in the developing nail organ where it is also defined by its expression for CD10. Its function may be related to the anchorage of the overlying nail bed but may also involve a more dynamic role in the induction of hard keratins in the latter, contributing to the formation of the nail plate.

The ventral proximal nail fold: stem cell niche of the nail and equivalent to the follicular bulge--a study on developing human skin.

BACKGROUND: Although the bulge is well characterized as a stem cell niche of the hair follicle, comparatively little is known about the location of stem cells in the nail. Herein, we describe the spatiotemporal expression pattern of six stem cell markers in the developing human nail and compared it with the embryonic and fetal human hair follicle. The areas of proliferative activity were additionally examined using labeling with Ki-67. METHODS: We examined immunohistochemically samples from embryonic and fetal human nail, hair and skin for the expression of cytokeratin 15 (CK15, two clones), cytokeratin 19 (CK19), PHLDA1, CD200, nestin and Ki-67 using standard techniques. RESULTS: CK15 (clone LHK15), CK19 and PHLDA1 are negative in the nail and hair matrix but positive in the ventral proximal nail fold and in the follicular bulge. Over the course of embryogenesis they display a highly specific spatiotemporal expression pattern both in the nail and in the hair follicle. CONCLUSIONS: We propose that at least during embryogenesis the proximal ventral nail fold represents the niche for the nail stem cells. In contrast to animal experiments, autoradiographic pulse-chasing studies cannot be performed in human, and immunohistochemical studies are a valid alternative although they have their limitations. Further studies on adult human nail units are suggested.

Sox9, more than a marker of the outer root sheath: spatiotemporal expression pattern during human cutaneous embryogenesis.

BACKGROUND: The sex-determining gene Sox9 was recently unexpectedly found to have an essential role in outer root sheath differentiation. It was also characterized as a general marker of basal cell carcinoma. Herein, we describe its spatiotemporal expression pattern outside the hair follicle during human cutaneous embryogenesis. METHODS: We examined immunohistochemically samples from embryonic and fetal human skin for the expression of SOX9 using standard techniques. For comparison reasons, we also included scalp skin from adults. RESULTS: SOX9 is expressed in the developing nail organ, eccrine glands, blood vessels and melanocytes/melanoblasts. In the nail organ, the nail bed but not the nail matrix was immunoreactive for SOX9. In plantar skin, SOX9 specifically labels the evolving eccrine glands but not the interfollicular keratinocytes. CONCLUSIONS: The distinctive expression pattern of SOX9 during human cutaneous embryogenesis indicates a key role in skin homeostasis that includes but goes beyond its role in outer root sheath differentiation. Studying immunohistochemical markers in developing human skin has the potential to further our understanding of adult skin physiology and to deepen our concepts especially of the histogenesis of adnexal tumors (including those of the nail unit) and the relationship of the various adnexal structures to each other.

Blimp-1: a marker of terminal differentiation but not of sebocytic progenitor cells.

BACKGROUND: The role of stem cells in maintaining the sebaceous gland throughout the various stages of life is not satisfactorily resolved. In a recent article, the transcription factor B lymphocyte-induced maturation protein 1 (Blimp-1) was proposed as a marker of a population of unipotent progenitor cells that reside in the sebaceous gland, regulating its size and activity. METHODS: We used standard immunohistochemical methods to examine Blimp-1 expression in samples from embryonic, fetal and adult human skin and in 119 sebaceous lesions comprising all major categories of sebocytic lineage, including hamartomas, cysts and benign and malignant neoplasms. RESULTS: Blimp-1 is expressed late in embryonic development and is restricted to the evolving sebaceous gland, the terminally differentiating components of the hair follicle and nail organ and the granular layer. This pattern is preserved into adult life. In all sebaceous lesions, Blimp-1 labels only the most mature cellular constituents. CONCLUSIONS: The reported expression pattern is difficult to reconcile with a function of Blimp-1 as a marker for sebocytic progenitor cells but indicates a major role in terminal differentiation. Within the interfollicular epidermis, its exclusive localization to the granular layer suggests a central function in skin barrier homeostasis in the human.

Basal cell (trichoblastic) carcinoma common expression pattern for epithelial cell adhesion molecule links basal cell carcinoma to early follicular embryogenesis, secondary hair germ, and outer root sheath of the vellus hair follicle: A clue to the adnexal nature of basal cell carcinoma?

BACKGROUND: Basal cell carcinoma (BCC) is still viewed by many dermatologists as a tumor of the interfollicular epidermis, although references were made early in the dermatopathologic literature to the resemblance of BCC to the hair follicle. OBJECTIVE: Our aim was to characterize the common expression pattern for the epithelial cell adhesion molecule (Ep-CAM) in BCCs, various stages of follicular embryogenesis, and adult hair follicles and, thereby, in analogy point to the similarity between BCC and the hair follicle. METHODS: We studied immunohistochemically 16 superficial BCCs for Ep-CAM and compared the expression pattern with that during hair follicle, nail, and eccrine gland development in human embryos and fetuses. In addition, we examined terminal scalp and vellus hair follicles. RESULTS: All BCCs expressed Ep-CAM similar to the early stages of the embryonic human hair follicle, the secondary hair germ, and the outer root sheath of the vellus hair follicle. The embryonic nail organ and the adult anagen hair follicles were completely negative. LIMITATIONS: The conclusions are based on the similarity in the immunohistochemical expression profile for a single adhesion molecule. CONCLUSION: BCC expresses the cell-cell adhesion molecule Ep-CAM similar to the embryonic hair germ, the secondary hair germ of the terminal hair follicle, and the outer root sheath of the vellus hair follicle. We suggest that this may be a clue to the adnexal nature of BCC and propose that BCC is the most primitive follicular tumor.

Psoriasis of the nail: anatomy, pathology, clinical presentation, and a review of the literature on therapy.

Psoriasis is a chronic skin disease that affects millions of people throughout the world. Even though cutaneous signs and symptoms are the most common clinical manifestations, the nails can be involved in up to 50% of cases, and their involvement remains an important yet often overlooked aspect of the disease. There is a broad spectrum of nail dystrophies associated with psoriasis, ranging from the common pitting and loosening of the nail plate to the less frequent discoloration and splinter hemorrhages seen in the nail bed. This article discusses the normal anatomy and embryology of the nail unit as well as the current understanding of the pathogenesis of the disease. It also provides an extensive review of the existing literature with respect to psoriatic nail therapy. Although there have been many recent advances in the treatment of the cutaneous form of the disease-most notably in the field of immunotherapies-the options for nail psoriasis are far more limited. While a number of treatment alternatives currently exist for nail disease, the general paucity of clear evidence regarding these choices often makes it difficult to select the most efficient, safe, and optimal treatment for the patient. Even though the current literature has shown some support for the use of topical, intralesional, radiation, systemic, and combination therapies for nail psoriasis, the available studies lack sufficient power to extrapolate a standardized therapeutic regimen. Therefore, until better-documented evidence validating the treatment options emerges within the literature, clinicians and patients are left with a vague and relatively unproven approach to psoriatic nail disease.

R-spondins in cutaneous biology: nails and cancer.

The R-spondins are a relatively recently identified family of secreted proteins linked to the Wnt signaling pathway. Recently, human phenotypes have been associated with mutations in two human R-spondins. Germline RSPO4 and RSPO1 mutations result in recessive anonychia (absence of all fingernails and toenails) and a recessive syndrome with XX-male sex reversal, PPK and a predisposition to SCC, respectively. This review discusses the key roles R-spondins play in embryogenesis, adult tissue maintenance and skin carcinogenesis.

Anatomic considerations of the human nail.

This article provides a description of the growth and anatomic structure of the human nails.

Patología ungueal en la infancia / Nail pathology in childhood

Las alteraciones ungueales en los niños representan un número de consultas no despreciable tanto en atención primaria y pediatría como en dermatología. Algunas alteraciones son idénticas a las de los adultos, pero existen otras que son características de esta etapa de la vida y que nos pueden ayudar en el diagnóstico. En este resumen describimos las principales alteraciones ungueales en la infancia

Disorders of the nail unit.

Nail disorders are often given little regard in clinical practice. The myriad relations between nail disease and other disease entities merits each practitioner's attention. Whether the cause is heritable, infectious, post-traumatic, environmental, neoplastic, biomechanical, or secondary to systemic disease, podiatrists are in a unique position to examine, properly diagnose, and treat nail disorders.

Anatomic considerations of the human nail.

The nail unit is distinctive for human beings. Developmentally, the fetus demonstrates cranial and caudal paired anlage of the upper and lower extremities. The leg bud develops a foot plate and eventually toe rays that are first notched, later webbed, and then develop into separate toes. Distal on the toe, the primitive nail unit appears and eventually moves dorsal. When developed fully, the nail unit consists of the nail plate, nail bed, ungualabia, eponychium, hyponychium, lunula, and nail matrix. These structures are associated intimately with the terminal or ungual phalanges of the foot's five toes.

Congenital anomalies of the nail unit.

The characteristic morphology of the nail unit is determined at the moment of conception by the chromosomal content of the zygote. Subsequent mitotic events including deletion, duplication, breakage, etc. also may contribute to nail deformity. In utero conditions are another factor that may affect the appearance of the nail unit. This article identifies conditions of the nail unit that are congenital in nature and deserve special attention to treatment plans that may or may not be beneficial.

Immunolocalization of epidermal growth factor receptors in normal developing human skin.

The embryogenesis of normal human skin is a complex process involving multiple cell types and developmentally regulated growth factors. The immunohistochemical localization of epidermal growth factor receptors (EGF-R) was studied in human fetal skin because this receptor modulates all known actions of EGF and TGF-alpha. EGF-R are present in developing skin as early as the 42nd day of gestation. Immunoreactive EGF-R are present in keratinocytes, endothelial, and skeletal muscle cells. In contrast to normal adult human skin in which the EGF-R are primarily restricted to the basal and immediately suprabasal keratinocytes, the fetal epidermis showed a persistent expression of EGF-R in all cell layers. The absence of EGF-R on the outer, apical surface of periderm cells that are exposed to amniotic fluid was unexpected and may reflect down-regulation of EGF-R by EGF/TGF-alpha or related fetal growth factors present in amniotic fluid. The complex regulation of EGF-R in embryonic hair follicles and sebaceous glands indicates an active and perhaps regulatory role for EGF/TGF-alpha in the development and function of pilosebaceous glands as well as mammalian skin in general.

Patterns of expression of trichocytic and epithelial cytokeratins in mammalian tissues. III. Hair and nail formation during human fetal development.

Cells forming hair and nail material are characterized by the synthesis of members of a particular group of alpha-keratin polypeptides (trichocytic cytokeratins. "T cytokeratins") different from epithelial cytokeratins ("E cytokeratins"). As the precursor cells to trichocytes are derived from fetal epidermal keratinocytes expressing only E cytokeratins, we have studied the patterns of expression of both T and E cytokeratins in developing human hair-and nail-forming tissues of different fetal stages, by immunocytochemistry using antibodies specific for certain T or E cytokeratins and by two-dimensional gel electrophoresis and immunoblotting. In developing hair follicles up to the early bulbous-peg stage (weeks 12-15 of gestational age), only certain E but no T cytokeratins were identified. T cytokeratins were first detected in the late bulbous-peg stage (in week-14 scalp skin) in certain cells of the central part of the hair cone. In hair-producing follicles (weeks 18-25), the lower hair matrix cells were positive for certain E cytokeratins, whereas T cytokeratins appeared in the uppermost portion of the matrix and, most prominently, in the maturing trichocytes. From the late bulbous-peg stage on. E cytokeratin antibody Ks13.1 selectively decorated the inner root sheath. In finger nail "anlagen", T cytokeratins were detected first in week 12 and 13 fetuses, specifically in cells of the lunula region. In more-advanced stages of nail formation, expression of T cytokeratins extended not only to the upper layers of the ventral nail matrix but was also found, albeit more sparsely, in cells of the whole nail-bed epithelium. Throughout these developmental stages, coexpression of T and E cytokeratins was noted in certain cells, including E cytokeratin 19. While in earlier stages E cytokeratins 10/11, characteristic of epidermal-type cornification, were noted in different regions, including the superficial stratum of the nail bed epithelium, they were later restricted to the epithelium of the proximal nail fold. The results show that terminal trichocytic differentiation starts, both in ontogeny and during the steady growth of hairs and nails, in cells expressing E cytokeratins and that coexpression of E and T polypeptides occurs in both kinds of appendages. While in the hair follicle, the change to the exclusive synthesis of T cytokeratins appears to take place relatively abruptly and simply, the development of nail structures from the ventral nail matrix seems to be more gradual and is characterized by more-complex patterns of coexpression of both kinds of cytokeratins.

The biology of human fetal skin at ages related to prenatal diagnosis.

It is the goal of the present article to review the state of knowledge of human skin development and to indicate some of the questions being approached in current studies of human fetal skin. Because of the breadth of the topic, the discussion will be limited to two ages during gestation that correspond to periods when samples of fetal skin or amniotic fluid cells (which in part are derived from the skin) are used to evaluate the condition of the fetus. These periods correspond to ages when amniocentesis (14-16 weeks) and fetoscopy accompanied by fetal skin biopsy (19-20 weeks) are performed.