RESUMEN
In this study, it was investigated how estrogens (17-beta-estradiol, E2) affect the estrogen receptor (ER) expression and gene regulation of male versus female human scalp hair follicles in vitro. Anagen VI follicles from frontotemporal scalp skin were microdissected and organ-cultured for up to 9 d in the presence of E2 (1-100 nm). Immunohistochemistry was performed for ERbeta-expression, known to be predominant in human scalp hair follicles, and for TGF-beta2-expression (as negative key hair growth modulator), and E2-responsive genes in organ-cultured human scalp hair follicles (48 h, 10 nM) were explored by cDNA microarray, using a commercial skin focus chip (Memorec, Cologne, Germany). The distribution pattern of ERbeta and TGF-beta2-immunoreactivity differed between male and female hair follicles after 48 h culture. Of 1300 genes tested, several genes were regulated sex-dependent differently. The study reveals substantial sex-dependent differences in the response of frontotemporal human scalp hair follicles to E2. Recognition and systematic dissection of the E2-dependent gene regulation will be crucial for the development of more effective, gender-tailored management strategies for female versus male pattern balding.
Asunto(s)
Estradiol/metabolismo , Receptor beta de Estrógeno/metabolismo , Folículo Piloso/metabolismo , Cuero Cabelludo/metabolismo , Alopecia/metabolismo , Alopecia/terapia , Estrógenos/metabolismo , Femenino , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Humanos , Inmunohistoquímica , Técnicas In Vitro , Masculino , Análisis de Secuencia por Matrices de Oligonucleótidos , Caracteres Sexuales , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
In mice, rats, and humans, loss of function of Foxn1, a member of the winged helix/forkhead family of transcription factors, leads to macroscopic nudity and an inborn dysgenesis of the thymus. Nude (Foxn1(nu)/Foxn1(nu)) mice develop largely normal hair follicles and produce hair shafts. However, presumably because of a lack of certain hair keratins, the hair shafts that are generated twist and coil in the hair follicle infundibulum, which becomes dilated. Since hair shafts fail to penetrate the epidermis, macroscopic nudity results and generates the - grossly misleading - impression that nude mice are hairless. Here, we provide an overview of what is known on the role of Foxn1 in mammalian skin biology, its expression patterns in the hair follicle, its influence on hair follicle function, and onychocyte differentiation. We focus on the mechanisms and signaling pathways by which Foxn1 modulates keratinocyte differentiation in the hair follicle and nail apparatus and summarize the current knowledge on the molecular and functional consequences of a loss of function of the Foxn1 protein in skin. Foxn1 target genes, gene regulation of Foxn, and pharmacological manipulation of the nude phenotype (e.g. by cyclosporine A, KGF, and vitamin D3) are discussed, and important open questions as well as promising research strategies in Foxn1 biology are defined. Taken together, this review aims at delineating why enhanced research efforts in this comparatively neglected field of investigative dermatology promise important new insights into the controls of epithelial differentiation in mammalian skin.
Asunto(s)
Factores de Transcripción Forkhead/fisiología , Folículo Piloso/metabolismo , Uñas/citología , Fenómenos Fisiológicos de la Piel , Animales , Diferenciación Celular/fisiología , Factores de Transcripción Forkhead/genética , Humanos , Ratones , Ratones Desnudos/anatomía & histología , Ratones Desnudos/genética , Ratones Desnudos/fisiología , Mutación , RatasRESUMEN
The transforming growth factor-beta family member activin is a potent regulator of skin morphogenesis and repair. Transgenic mice overexpressing activin in keratinocytes display epidermal hyper-thickening and dermal fibrosis in normal skin and enhanced granulation tissue formation after wounding. Mice overexpressing the secreted activin antagonist follistatin, however, have the opposite wound-healing phenotype. To determine whether activin affects skin morphogenesis and repair via activation of keratinocytes and/or stromal cells, we generated transgenic mice expressing a dominant-negative activin receptor IB mutant (dnActRIB) in keratinocytes. The architecture of adult skin was unaltered in these mice, but delays were observed in postnatal pelage hair follicle morphogenesis and in the first catagen-telogen transformation of hair follicles. Although dnActRIB-transgenic mice showed slightly delayed wound re-epithelialization after skin injury, the strong inhibition of granulation tissue formation seen in follistatin-transgenic mice was not observed. Therefore, although endogenous activin appeared to affect skin morphogenesis and repair predominantly via stromal cells, overexpressed activin strongly affected the epidermis. The epidermal phenotype of activin-overexpressing mice was partially rescued by breeding these animals with dnActRIB-transgenic mice. These results demonstrate that activin affects both stromal cells and keratinocytes in normal and wounded skin and that the effect on keratinocytes is dose-dependent in vivo.
Asunto(s)
Activinas/fisiología , Queratinocitos/fisiología , Fenómenos Fisiológicos de la Piel , Células del Estroma/fisiología , Cicatrización de Heridas/fisiología , Animales , División Celular , Células Cultivadas , Epidermis/fisiología , Expresión Génica , Genes Dominantes , Folículo Piloso/anomalías , Subunidades beta de Inhibinas/metabolismo , Queratinocitos/citología , Queratinocitos/metabolismo , Ratones , Ratones Transgénicos , Concentración Osmolar , Fenotipo , Proteínas/genética , Proteínas/metabolismo , Transducción de Señal , Piel/citología , Piel/crecimiento & desarrollo , Células del Estroma/citología , TransgenesRESUMEN
Since mammalian skin expresses the enzymatic apparatus for melatonin synthesis, it may be an extrapineal site of melatonin synthesis. However, evidence is still lacking that this is really the case in situ. Here, we demonstrate melatonin-like immunoreactivity (IR) in the outer root sheath (ORS) of mouse and human hair follicles (HFs), which corresponds to melatonin, as shown by radioimmunoassay and liquid chromatography/tandem mass spectrometry (LC/MS/MS). The melatonin concentration in organ-cultured mouse skin, mouse vibrissae follicles, and human scalp HFs far exceeds the respective melatonin serum level and is significantly increased ex vivo by stimulation with norepinephrine (NE), the key stimulus for pineal melatonin synthesis. By real-time PCR, transcripts for the melatonin membrane receptor MT2 and for the nuclear mediator of melatonin signaling, retinoid orphan receptor alpha (ROR)alpha, are detectable in murine back skin. Transcript levels for these receptors fluctuate in a hair cycle-dependent manner, and are maximal during apoptosis-driven HF regression (catagen). Melatonin may play a role in hair cycle regulation, since its receptors (MT2 and RORalpha) are expressed in murine skin in a hair cycle-dependent manner, and because it inhibits keratinocyte apoptosis and down-regulates ERalpha expression. Therefore, the HF is both, a prominent extrapineal melatonin source, and an important peripheral melatonin target tissue. Regulated intrafollicular melatonin synthesis and signaling may play a previously unrecognized role in the endogenous controls of hair growth, for example, by modulating keratinocyte apoptosis during catagen and by desensitizing the HF to estrogen signaling. As a prototypic neuroectodermal-mesodermal interaction model, the HF can be exploited for dissecting the obscure role of melatonin in such interactions in peripheral tissues.
Asunto(s)
Ectodermo/metabolismo , Folículo Piloso/embriología , Melatonina/fisiología , Mesodermo/metabolismo , Neuronas/metabolismo , Receptores de Melatonina/metabolismo , Animales , Apoptosis , Cromatografía Liquida , Regulación hacia Abajo , Receptor alfa de Estrógeno/metabolismo , Femenino , Cabello/fisiología , Folículo Piloso/metabolismo , Humanos , Inmunoensayo/métodos , Inmunohistoquímica , Queratinocitos/metabolismo , Espectrometría de Masas , Melatonina/química , Melatonina/metabolismo , Ratones , Ratones Endogámicos C57BL , Técnicas de Cultivo de Órganos/métodos , ARN Mensajero/metabolismo , Proteínas Tirosina Quinasas Receptoras , Receptores Huérfanos Similares al Receptor Tirosina Quinasa , Receptores de Superficie Celular/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal , Piel/citología , Piel/metabolismoRESUMEN
Follicular papilla (FP) cells, but not their closely related dermal fibroblasts, can maintain hair growth suggesting cell type-specific molecular signals. To define the molecular differences between these two cell types, we generated a subtraction complementary DNA (cDNA) library highly enriched in FP-specific cDNA. Differential screening identified FP-1 as the most abundant cDNA sequence in this subtraction library. FP-1 message RNA is highly abundant in cultured rat vibrissa FP cells, can be detected at very low levels in the stomach and the ovary, and is undetectable in cultured dermal fibroblasts and in 16 rat non-follicular tissues. The full-length, 2.3 kb FP-1 cDNA encodes a protein of 549 amino acids harboring a signal peptide, collagen triple helix repeats, and an olfactomedin-like domain. Monospecific rabbit antibodies to FP-1 recognize in cultured FP cells a single approximately 72 kDa glycoprotein with a approximately 60 kDa protein core. FP-1 protein is expressed in vivo in a hair cycle-dependent manner, as it can be detected in FP during anagen, but not in catagen and telogen phases of the hair cycle. FP-1 is presumably a highly specific extracellular matrix protein synthesized by FP cells and may be involved in the organization of FP during certain phases of normal or pathological hair growth.