Alkaline ceramidase 1 is essential for mammalian skin homeostasis and regulating whole-body energy expenditure.

The epidermis is the outermost layer of skin that acts as a barrier to protect the body from the external environment and to control water and heat loss. This barrier function is established through the multistage differentiation of keratinocytes and the presence of bioactive sphingolipids such as ceramides, the levels of which are tightly regulated by a balance of ceramide synthase and ceramidase activities. Here we reveal the essential role of alkaline ceramidase 1 (Acer1) in the skin. Acer1-deficient (Acer1(-/-) ) mice showed elevated levels of ceramide in the skin, aberrant hair shaft cuticle formation and cyclic alopecia. We demonstrate that Acer1 is specifically expressed in differentiated interfollicular epidermis, infundibulum and sebaceous glands and consequently Acer1(-/-) mice have significant alterations in infundibulum and sebaceous gland architecture. Acer1(-/-) skin also shows perturbed hair follicle stem cell compartments. These alterations result in Acer1(-/-) mice showing increased transepidermal water loss and a hypermetabolism phenotype with associated reduction of fat content with age. We conclude that Acer1 is indispensable for mammalian skin homeostasis and whole-body energy homeostasis. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Genetically modified laboratory mice with sebaceous glands abnormalities.

Sebaceous glands (SG) are exocrine glands that release their product by holocrine secretion, meaning that the whole cell becomes a secretion following disruption of the membrane. SG may be found in association with a hair follicle, forming the pilosebaceous unit, or as modified SG at different body sites such as the eyelids (Meibomian glands) or the preputial glands. Depending on their location, SG fulfill a number of functions, including protection of the skin and fur, thermoregulation, formation of the tear lipid film, and pheromone-based communication. Accordingly, SG abnormalities are associated with several diseases such as acne, cicatricial alopecia, and dry eye disease. An increasing number of genetically modified laboratory mouse lines develop SG abnormalities, and their study may provide important clues regarding the molecular pathways regulating SG development, physiology, and pathology. Here, we summarize in tabulated form the available mouse lines with SG abnormalities and, focusing on selected examples, discuss the insights they provide into SG biology and pathology. We hope this survey will become a helpful information source for researchers with a primary interest in SG but also as for researchers from unrelated fields that are unexpectedly confronted with a SG phenotype in newly generated mouse lines.

Sebaceous gland, hair shaft, and epidermal barrier abnormalities in keratosis pilaris with and without filaggrin deficiency.

Although keratosis pilaris (KP) is common, its etiopathogenesis remains unknown. KP is associated clinically with ichthyosis vulgaris and atopic dermatitis and molecular genetically with filaggrin-null mutations. In 20 KP patients and 20 matched controls, we assessed the filaggrin and claudin 1 genotypes, the phenotypes by dermatoscopy, and the morphology by light and transmission electron microscopy. Thirty-five percent of KP patients displayed filaggrin mutations, demonstrating that filaggrin mutations only partially account for the KP phenotype. Major histologic and dermatoscopic findings of KP were hyperkeratosis, hypergranulosis, mild T helper cell type 1-dominant lymphocytic inflammation, plugging of follicular orifices, striking absence of sebaceous glands, and hair shaft abnormalities in KP lesions but not in unaffected skin sites. Changes in barrier function and abnormal paracellular permeability were found in both interfollicular and follicular stratum corneum of lesional KP, which correlated ultrastructurally with impaired extracellular lamellar bilayer maturation and organization. All these features were independent of filaggrin genotype. Moreover, ultrastructure of corneodesmosomes and tight junctions appeared normal, immunohistochemistry for claudin 1 showed no reduction in protein amounts, and molecular analysis of claudin 1 was unremarkable. Our findings suggest that absence of sebaceous glands is an early step in KP pathogenesis, resulting in downstream hair shaft and epithelial barrier abnormalities.

Fifty years of the asebia mouse: origins, insights and contemporary developments.

First described as an alopecic spontaneous mutant mouse line lacking sebaceous glands in a publication in Science in 1965 by Allen H. Gates and Marvin Karasek, asebia mice soon became a popular tool for rodent sebaceous gland research. In addition to the study of sebaceous lipids, the original asebia mice and subsequent allelic mutations were widely employed to examine the influence of the sebaceous gland on hair growth, epidermal proliferation, dermal inflammation and skin carcinogenesis, among other aspects. With the identification of Scd1 gene mutations as the genetic basis of the asebia phenotype and with the advent of more refined methods for manipulating the mouse genome, asebia mice progressively lost importance. However, they contributed to, or even provided the initial spark for, several current research topics. These include the role of the sebaceous gland in hair shaft-sheath interaction and its significance for cicatricial alopecia, and the antimicrobial activity of sebum. Furthermore, mice with skin-specific deletion of SCD1, which have increased energy expenditure and are protected from high fat diet-induced obesity, provided novel insights into the crosstalk between the skin and peripheral tissues in maintaining energy homeostasis. In briefly reviewing its story, this commentary pays tribute to asebia mice and to the original publication in its golden anniversary year.

Extensive comedonal and cystic acne in Patau syndrome.

Patau syndrome is a chromosomal disorder associated with multiple malformations caused by inheritance of an extra chromosome (trisomy 13). Some skin defects have been reported in patients with Patau syndrome, such as scalp defects, glabellar stains, deep palmar creases, rocker-bottom feet, convex soles, hyperconvextity of the nails, and multiple hemangiomas. To our knowledge, widespread comedonal and cystic acne have not been previously reported in Patau syndrome.

gamma-secretase functions through Notch signaling to maintain skin appendages but is not required for their patterning or initial morphogenesis.

The role of Notch signaling during skin development was analyzed using Msx2-Cre to create mosaic loss-of-function alleles with precise temporal and spatial resolution. We find that gamma-secretase is not involved in skin patterning or cell fate acquisition within the hair follicle. In its absence, however, inner root sheath cells fail to maintain their fates and by the end of the first growth phase, the epidermal differentiation program is activated in outer root sheath cells. This results in complete conversion of hair follicles to epidermal cysts that bears a striking resemblance to Nevus Comedonicus. Sebaceous glands also fail to form in gamma-secretase-deficient mice. Importantly, mice with compound loss of Notch genes in their skin phenocopy loss of gamma-secretase in all three lineages, demonstrating that Notch proteolysis accounts for the major signaling function of this enzyme in this organ and that both autonomous and nonautonomous Notch-dependent signals are involved.

Hair cycle and wound healing in mice with a keratinocyte-restricted deletion of FAK.

Focal adhesion kinase (FAK) is a critical component in transducing signals downstream of both integrins and growth factor receptors. To determine how the loss of FAK affects the epidermis in vivo, we have generated a mouse model with a keratinocyte-restricted deletion of fak (FAKK5 KO mice). FAK(K5 KO) mice displayed three major phenotypes--irregularities of hair cycle, sebaceous glands hypoplasia, and a thinner epidermis--pointing to defects in the proliferative capacity of multipotent stem cells found in the bulge. FAK-null keratinocytes in conventional primary culture undergo massive apoptosis hindering further analyses, whereas the defects observed in vivo do not shorten the mouse lifespan. These results suggest that the structure and the signaling environment of the native tissue may overcome the lack of signaling through FAK. Our findings point to the importance of in vivo and three-dimensional in vitro models in analyses of cell migration, proliferation, and survival. Surprisingly, the difference between FAKloxP/+ and FAKK5 KO mice in wound closure was not statistically significant, suggesting that in vivo loss of FAK does not affect migration/proliferation of basal keratinocytes in the same way as it affects multipotent stem cells of the skin.

Leptin modulates the effects of acyl CoA:diacylglycerol acyltransferase deficiency on murine fur and sebaceous glands.

Acyl CoA:diacylglycerol acyltransferase (DGAT) is a ubiquitously expressed enzyme that catalyzes the final reaction in the major pathways of triglyceride synthesis. Mice lacking DGAT1 (Dgat(-/-)) demonstrate significant changes in lipid metabolism in several tissues, including the skin. Here we report the effects of DGAT1 deficiency on fur and sebaceous glands. Adult Dgat(-/-) mice had dry fur and hair loss, which were associated with atrophic sebaceous glands and fur lipid abnormalities. As a result, Dgat(-/-) mice had impaired water repulsion and defective thermoregulation after water immersion. These phenotypes were mostly absent in Dgat(-/-) mice with leptin deficiency, indicating an unexpected role for leptin in modulating the skin phenotype. Our findings indicate that DGAT1 plays an important role in normal fur and sebaceous gland physiology and provide evidence that leptin modulates these processes in the skin.

Sebaceous gland hyperplasia on rabbit pinna induced by tetradecane.

To investigate the pathologic changes of sebaceous glands during comedo formation induced by topically applied substances in a rabbit pinna model, purified tetradecane was inuncted on the ventral aspect of the rabbit pinnas once a day for a week. Histologically, a marked hyperplasia of sebaceous glands, epidermis, and follicular epithelium was seen. These remarkably enlarged sebaceous glands were examined histochemically and ultrastructurally. The acinus size and cell population of the hyperplastic sebaceous gland were significantly increased over those of the normal sebaceous gland. By N-(7-dimethylamino-4-methyl-3-coumarinyl)maleimide staining, normal distribution patterns of sulfhydryl (SH) and disulfide (SS) were seen in the peripheral to differentiating layers in the hyperplastic sebaceous glands. In the terminally differentiated layer, the brilliant SH fluorescence was gradually decreased and the SS fluorescence was gradually increased in intensity, indicating that most SH groups in the sebaceous cells were converted to SS linkages before holocrine secretion. By transmission electron microscopy, several cell layers of undifferentiated sebaceous cells were observed at the periphery of the large sebaceous gland. The differentiating sebaceous cells produced a large number of lipid droplets, which were produced in either rough or smooth endoplasmic reticulum. These cells were abruptly converted into homogeneously electron-dense cells which formed several layers. These homogeneous cells gradually lost their electron density before holocrine secretion. These findings indicate that the sebaceous cells in the hyperplastic sebaceous glands undergo a magnified step-by-step cell differentiation and play a role in slightly modified lipid formation, and that there may be an increased production of sebum in the rabbit pinna model. This is the first report of sebaceous hyperplasia induced by a topically applied substance on skin surface, except for androgens. The hyperplastic sebaceous glands could serve as a model for investigations of sebaceous cell differentiation and lipid formation.

Defolliculated (dfl): a dominant mouse mutation leading to poor sebaceous gland differentiation and total elimination of pelage follicles.

Defolliculated is a novel spontaneous mouse mutation that maps to chromosome 11 close to the type I keratin locus. Histology shows abnormal differentiation of the sebaceous gland, with the sebocytes producing little or no sebum and undergoing abnormal cornification. The hair follicles fail to regress during catagen leading to abnormally long follicles. In contrast the hair shafts are shorter than normal, suggesting altered differentiation or proliferation of matrix cells during anagen. The shafts emerge from the follicle with cornified material still attached. The dermis contains increased numbers of immune cells, including T cells (CD4-positive), macrophages, and mast cells, at all time points examined. Complete elimination of all pelage and tail follicles occurs after two to three hair cycles, apparently by necrosis. Defolliculated may be a useful model for determining further functions of the sebaceous gland, and for understanding the regulation of catagen and hair follicle immunology.

Absence of dermal ridge patterns: genetic heterogeneity.

An apparently new form of complete absence of dermal ridge patterns was transmitted as an autosomal dominant trait through five generations in an Irish-American family. Affected individuals lacked dermatoglyphic patterns, sweat pores, and ability to sweat in the volar areas of the fingertips, palms, and soles. They also had congenital milia and blisters on the fingertips and soles at birth, abnormal nails, single transverse palmar creases, increased heat tolerance, and painful fissures in adult life around the fingernails in cold weather.

Ectopic gingival sebaceous glands presenting as localized periodontitis.

The development of ectopic gingival sebaceous glands is a very unusual condition which is histologically similar to Fordyce's granules when they occur within the buccal or labial mucosa. In this report, we present a rare case of ordinarily innocuous, ectopic gingival sebaceous glands, which presented clinically and radiographically as localized advanced periodontitis. Histological and immunocytochemical evaluation of tissue removed from the periodontal lesion following excisional biopsy supported the diagnosis of an ectopic gingival sebaceous defect. This case illustrates the necessity of considering less frequently occurring entities in the differential diagnosis of localized lesions which appear to be periodontal in origin.

Occurrence of oral sebaceous glands in 43,654 industrial workers of Gujarat, India.

In 10 cancer patients platelet concentration, platelet consumption, platelet half-life time and plasma concentration of platelet factor 4 were determined. A high frequency of thrombocytosis and increased platelet consumption were observed, and the plasma concentration of platelet factor 4 was increased. However, no significant correlation was found between platelet consumption and the result of a single determination of platelet factor 4 concentrations in plasma.

Odontotrichodysplasia: a case report with a review of conditions combining ectodermal dysplasia (subgroup 1-2) with skin manifestations.

We report a 5-year-old girl with partial anodontia, hypotrichosis, hyperpigmentation of the skin, absence of pilosebaceous structures, and long thin fingers. There has as yet been, to the best of our knowledge, no report of such a combination of features. A review of conditions combining ectodermal dysplasia (subgroup 1-2) with skin manifestations is presented.

Lingual sebaceous glands: report of case.

A 28-year-old dentist noticed a 9X5-mm yellow submucosal plaque in the midlateral dorsum of his tongue. After a period of observation an excisional biopsy was performed. The histopathologic examination of the specimen revealed normal sebaceous glands opening onto the tongue surface. This occurrence of ectopic sebaceous glands in the tongue is notably rare in contrast with their frequent occurrence in the lips and buccal mucosa.