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Biomedical subjects

R Paus

Publications and source records attributed to R Paus.

At least 55 records · Page 3Linked to original sources
PubMed2000

Expression of galectin-1 and -3 and of accessible binding sites during murine hair cycle.

Although protein-carbohydrate interactions are supposed to play key roles in cell adhesion, signalling and growth control. Their exact role in skin physiology has only recently been investigated. The endogenous lectins galectin-1 and galectin-3 have been identified in skin including hair follicles. Here, we analyzed the expression and distribution of these galectins and their binding sites in C57BL/6 mice during hair cycle. The expression of galectin-1 and galectin-3 binding sites was found to be predominantly hair cycle-dependent showing some overlapping to the expression of galectin-1 and -3. The outer root sheath (ORS) expressed galectin-1 binding sites during anagen IV to VI and in early catagen, whereas galectin-1 was expressed from early anagen to late catagen. The ORS expressed galectin-3 binding sites during catagen transition corresponding to a galectin-3 expression during anagen V and catagen. The innermost layer of the ORS expressed galectin-3 binding sites during anagen VI until catagen VIII, but galectin-3 during anagen III to IV and catagen. The inner root sheath (IRS) expressed galectin-3 binding sites only in anagen IV but missed expression of any of the two galectins. The matrix cells expressed galectin-3 binding sites in catagen II-III as well as galectin-3 during anagen V to catagen IV. The present study provides the first evidence for a cycle-related expression of both galectin-1 and -3 and their binding sites during murine hair cycle.

Animals↗
PubMed1999

A role for p75 neurotrophin receptor in the control of hair follicle morphogenesis.

During hair follicle (HF) morphogenesis, p75 neurotrophin receptor (p75NTR) reportedly is the first growth factor receptor found to be expressed by those fibroblasts that later develop into the dermal papilla (DP) of the HF. However, the functional role of p75NTR in HF morphogenesis is still unknown. Studying HF development in fetal and neonatal C57BL/6 murine back skin, we show that p75NTR-immunoreactivity (IR) is prominently expressed by DP fibroblasts as well as by skin nerves during the early steps of HF development. In contrast, p75NTR-IR disappears from the DP in the fully developed HF and it is expressed only in the epithelial outer root sheath of the HF. Compared to age-matched wild-type animals, p75NTR knockout (-/-) mice show significant acceleration of HF morphogenesis, and DP fibroblasts of p75NTR knockout mice show reduced proliferative activity in situ, indicating alterations in their transition from proliferation to differentiation. Although no significant differences in the expression of adhesion molecules (NCAM), selected morphogens (TGFbeta-2, HGF/SF, FGF-2, KGF), or their receptors (TGFbetaR-II, m-met, FGFR-1) were seen between DP of p75NTR knockout and wild-type mice, p75NTR mutants showed a prominent upregulation of FGFR-2, a high-affinity receptor for KGF, in both follicular DP and epithelium. Furthermore, the administration of anti-KGF neutralizing antibody significantly inhibited acceleration of HF morphogenesis in p75NTR knockout mice in vivo. These observations suggest that p75NTR plays an important role during HF morphogenesis, functioning as a receptor that negatively controls HF development, most likely via alterations in DP fibroblast proliferation/differentiation and via downregulation of KGF/FGFR-2 signaling in the HF.

Animals↗
PubMed1999

Cutaneous expression of CRH and CRH-R. Is there a "skin stress response system?".

The classical neuroendocrine pathway for response to systemic stress is by hypothalamic release of corticotropin releasing hormone (CRH), subsequent activation of pituitary CRH receptors (CRH-R), and production and release of proopiomelanocortin (POMC) derived peptides. It has been proposed that an equivalent to the hypothalamic-pituitary-adrenal axis functions in mammalian skin, in response to local stress (see Reference 1). To further define such system we used immunocytochemistry, RP-HPLC separation, and RIA techniques, in rodent and human skin, and in cultured normal and malignant melanocytes and keratinocytes. Production of mRNA for CRH-R1 was documented in mouse and human skin using RT-PCR and Northern blot techniques; CRH binding sites and CRH-R1 protein were also identified. Addition of CRH to immortalized human keratinocytes, and to rodent and human melanoma cells induced rapid, specific, and dose-dependent increases in intracellular Ca2+. The latter were inhibited by the CRH antagonist alpha-helical-CRH(9-41) and by the depletion of extracellular calcium with EGTA. CRH production was enhanced by ultraviolet light radiation and forskolin (a stimulator for intracellular cAMP production), and inhibited by dexamethasone. Thus, evidence that skin cells, both produce CRH and express functional CRH-R1, supports the existence of a local CRH/CRH-R neuroendocrine pathway that may be activated within the context of a skin stress response system.

Animals↗
PubMed1999

The skin POMC system (SPS). Leads and lessons from the hair follicle.

Human and murine skin are prominent extrapituitary sources and targets for POMC products. The expression of, for example, ACTH, alpha-MSH, beta-endorphin, and MC-1-receptors fluctuates during synchronized hair follicle cycling in C57BL/6 mice. Since hair growth can be induced by ACTH injections in mice and mink, and since high doses of MSH peptides modulate epidermal and/or follicle keratinocyte proliferation in murine skin organ culture, some POMC products may operate as locally generated growth modulators, in addition to their roles in cutaneous pigment and immunobiology. Intrafollicularly generated ACTH and alpha-MSH as well as their cognate receptors may assist in the maintenance of the peculiar immune privilege of the anagen hair bulb. Possibly, they are also involved in the development of the follicle pigmentary unit, with whose generation their expression coincides. Given that murine skin also expresses (in a hair-cycle-dependent way) CRH and CRH-R, which control pituitary POMC expression and in view of the fact that CRH arrests follicles in telogen, this suggests the existence of a local skin POMC system (SPS). This may be an integral component of cutaneous stress response-systems, and may most instructively be studied using the murine hair cycle as a model.

Adrenocorticotropic Hormone↗
PubMed1999

The TGF-beta2 isoform is both a required and sufficient inducer of murine hair follicle morphogenesis.

Hair follicle development serves as an excellent model to study control of organ morphogenesis. Three specific isoforms of TGF-beta exist which exhibit a distinct pattern of expression during hair follicle morphogenesis. To clarify the still elusive role of these factors in hair follicle development, we have used a combined genetic and functional approach: analysis of hair follicle development in mice with disruptions of the TGF-beta1, 2, and 3 genes was coupled with a direct functional test of the effect of added purified factors on fetal hair follicle development in skin organ cultures. TGF-beta2 null mice exhibited a profound delay of hair follicle morphogenesis, with a 50% reduced number of hair follicles. In contrast to hair follicle development, growth and differentiation of interfollicular keratinocytes proceeded unimpaired. Unlike TGF-beta2-/- mice, mice with a disruption of the TGF-beta1 gene showed slightly advanced hair follicle formation, while lack of the TGF-beta3 gene did not have any effects. Treatment of wild-type, embryonic skin explants (E14.5 or E15.5) with TGF-beta2 protein in either soluble form or slow release beads induced hair follicle development and epidermal hyperplasia, while similar TGF-beta1 treatment exerted suppressive effects. Thus, the TGF-beta2 isoform plays a specific role, not shared by the other TGF-beta isoforms, as an inducer of hair follicle morphogenesis and is both required and sufficient to promote this process.

Animals↗
PubMed1999

Human monocytes constitutively express membrane-bound, biologically active, and interferon-gamma-upregulated interleukin-15.

Interleukin-15 (IL-15) is a potent regulator of T-, B-, and natural killer cell proliferation and displays unusually tight controls of secretion. Even though IL-15 mRNA is constitutively expressed in monocytes/macrophages and is upregulated by a variety of stimuli, evidence for IL-15 cytokine secretion is only found exceptionally, eg, conditions of pathological, chronic inflammation. This raises the possibility that monocytes express membrane-bound IL-15 rather than secrete it. The current study explores this hypothesis. We demonstrate here that biologically active IL-15 is indeed detectable in a constitutively expressed, membrane-bound form on normal human monocytes, as well as on monocytic cell lines (MONO-MAC-6, THP-1, and U937), but not on human T or B cells (MT4, M9, C5966, JURKAT, DAUDI, RAJI, and Epstein-Barr virus-immortalized B-cell clones). Furthermore, cell surface-bound IL-15 is upregulated upon interferon-gamma stimulation. Interestingly, monocyte/macrophage inhibitory cytokines such as IL-4 and IL-13 fail to downregulate both constitutive and induced cell-surface expression of IL-15. Membrane-bound IL-15 does not elute with acetate buffer or trypsin treatment, suggesting that it is an integral membrane protein and that it is not associated with the IL-15 receptor complex. Finally, membrane-bound IL-15 stimulates T lymphocytes to proliferate in vitro, indicating that it is biologically active. These findings enlist IL-15 in the fairly small family of cytokines for which the presence of a biologically active membrane-bound form has been demonstrated (eg, IL-1, tumor necrosis factor-alpha, and IL-10) and invites the speculation that most of the biological effects of IL-15 under physiological conditions are exerted by the cell surface-bound form.

Cells, Cultured↗
PubMed1999

The role of the hairless (hr) gene in the regulation of hair follicle catagen transformation.

Mice that carry a mutation at the hairless (hr) locus develop seemingly normal hair follicles (HF) but shed their hairs completely soon after birth. Histologically, their HFs degenerate into characteristic utriculi and dermal cysts shortly after the entry of the HF into the first regression phase (catagen), during the initiation of HF cycling. Here, we show that at least nine distinct stages of HF disintegration can be distinguished in hr/hr mice. Toward the end of HF morphogenesis (day 15 postpartum) the proximal hair bulb in hr/hr skin undergoes premature and massive apoptosis. This is associated with a dyscoordination of cell proliferation in defined HF compartments, malpositioning of the proximal inner root sheath, striking atrophy of outer root sheath, and failure of trichilemmal keratinization in the developing club hair. Rather than undergoing their normal catagen-associated involution, the hair bulb and central outer root sheath disintegrate into separate cell clusters, thus disrupting all epithelial contact with the dermal papilla. Dermal papilla fibroblasts fail to migrate upward, and break up into clusters of shrunken cells stranded in the reticular dermis as dermal cyst precursors, while the upper HF epithelium transforms into utriculi. Some dermal papilla cells, which normally never undergo apoptosis, also become TUNEL+ in hr/hr skin, and their normally high expression of a key adhesion molecule, neural cell adhesion molecule, declines. Thus, loss of a functional hr gene product (a putative zinc finger transcription factor) initiates a premature, highly dysregulated catagen, which results in the destruction of the normal HF architecture and abrogates the HF's ability to cycle. This provides new insights into the pathobiology of the hr mutation, and suggests that the normal hr gene product is a crucial element of catagen control.

Alkaline Phosphatase↗
PubMed1999

Abundant production of brain-derived neurotrophic factor by adult visceral epithelia. Implications for paracrine and target-derived Neurotrophic functions.

Brain-derived neurotrophic factor (BDNF) plays a crucial role for the survival of visceral sensory neurons during development. However, the physiological sources and the function of BDNF in the adult viscera are poorly described. We have investigated the cellular sources and the potential role of BDNF in adult murine viscera. We found markedly different amounts of BDNF protein in different organs. Surprisingly, BDNF levels in the urinary bladder, lung, and colon were higher than those found in the brain or skin. In situ hybridization experiments revealed that BDNF mRNA was made by visceral epithelial cells, several types of smooth muscle, and neurons of the myenteric plexus. Epithelia that expressed BDNF lacked both the high- and low-affinity receptors for BDNF, trkB and p75(NTR). In contrast, both receptors were present on neurons of the peripheral nervous system. Studies with BDNF-/-mice demonstrated that epithelial and smooth muscle cells developed normally in the absence of BDNF. These data provide evidence that visceral epithelia are a major source, but not a target, of BDNF in the adult viscera. The abundance of BDNF protein in certain internal organs suggests that this neurotrophin may regulate the function of adult visceral sensory and motor neurons.

Animals↗
PubMed1999

Noggin is a mesenchymally derived stimulator of hair-follicle induction.

The induction of developmental structures derived from the ectoderm, such as the neural tube or tooth, occurs through neutralization of the inhibitory activity of members of the bone-morphogenetic protein (BMP) family by BMP antagonists. Here we show that, during hair-follicle development, the neural inducer and BMP-neutralizing protein Noggin is expressed in the follicular mesenchyme, that noggin-knockout mice show significant retardation of hair-follicle induction, and that Noggin neutralizes the inhibitory action of BMP-4 and stimulates hair-follicle induction in embryonic skin organ culture. As a crucial mesenchymal signal that stimulates hair-follicle induction, Noggin operates through antagonistic interactions with BMP-4, which result in upregulation of the transcription factor Lef-1 and the cell-adhesion molecule NCAM, as well as through BMP4-independent downregulation of the 75 kD neurotrophin receptor in the developing hair follicle.

Animals↗
PubMed1999

Immunology of the hair follicle: a short journey into terra incognita.

This paper delineates briefly why the immunology of the hair follicle matters (e.g., anti-infection defense, hair growth control by immunomodulatory agents, sequestration of follicular autoantigens), and which open key questions await clarification. We then focus on the murine hair follicle immune system (HIS) and its immune privilege. We show how the murine HIS is gradually constructed during hair follicle morphogenesis, and how it is transformed during hair follicle cycling. Key characteristics of the HIS are summarized, such as the absence of MHC class I expression in the anagen hair bulb and the very restricted distribution of antigen-presenting cells and intraepithelial T cells to the distal outer root sheath, which also expresses nonclassical MHC class Ib molecules. The interconnections between the HIS and the skin immune system (SIS) and potential hair growth-modulatory roles of mast cells and macrophages are addressed, and very recent findings on the human HIS are summarized. The paper closes by sketching immunobiologic, clinical, and pharmacologic perspectives in trichoimmunology that deserve the attention of immunologists, dermatologists, and hair biologists alike.

Animals↗
PubMed1999

Hair follicle apoptosis and Bcl-2.

Hair follicle (HF) morphogenesis and cycling are characterized by a tightly controlled balance of proliferation, differentiation and apoptosis. The members of the bcl-2 family of proto-oncogenes are important key players in the apoptosis control machinery of most cell types. Bcl-2, an apoptosis inhibitor, and Bax, an apoptosis promoter, show tightly regulated, hair cycle-dependent expression patterns: during catagen, the distal ORS of the HF remains strongly positive for Bcl-2 and Bax; in contrast, the proximal epithelial part of the HF loses most Bcl-2 expression while it remains strongly positive for Bax. In Bcl-2 null mice, skin becomes markedly hypopigmented during the first postnatal anagen probably due to increased melanocyte apoptosis. Reportedly, these mice also show a retardation of the first anagen development after birth. Transgenic mice overexpressing Bcl-2 under the control of the keratin-1 promoter display multifocal epidermal hyperplasia and aberrant expression of keratin-6, while alterations of HF cycling have not been investigated. Surprisingly, Bcl-2 overexpression under the control of the keratin-14 promoter leads to accelerated catagen progression and increased chemotherapy-induced apoptosis, HF dystrophy and alopecia. Transgenic mice overexpressing Bcl-X(L), another anti-apoptotic bcl-2 family member, under the control of the K14 promoter, reportedly also display accelerated catagen development. These and other Bcl-2 transgenic and null mice are now available to further dissect the as yet unclear, and likely complex, role of Bcl-2 in HF growth and pigmentation.

Animals↗
PubMed1999

The fate of hair follicle melanocytes during the hair growth cycle.

The fate of the follicular pigmentary unit during the hair growth cycle has long been one of the great enigmas of both hair follicle and pigment cell biology. Although melanocytes are distributed in several different compartments of the anagen hair follicle, melanogenically active cells are located only in the hair bulb, where they are directly involved in hair shaft pigmentation. These pigment cells are readily detectable only when they become melanogenically active during anagen III of the hair growth cycle. Thus, their status during hair follicle regression (catagen), when melanogenesis is switched off, until they re-appear again as pigment-producing cells in the anagen III hair follicle, has remained poorly defined. Historically, it has been proposed that hair bulb melanocytes adopt a self-perpetuating, catagen-resistant strategy of de-differentiation during hair follicle regression and re-differentiation upon entry into a new anagen phase; however, this explanation remains problematic in the absence of evidence for de-differentiation/re-differentiation plasticity in most nonmalignant cell systems.

Animals↗
PubMed1999

Chronobiology of the hair follicle: hunting the " hair cycle clock".

The hair follicle (HF) is the only mammalian organ that undergoes life-long, cyclic transformations from long stages of growth (anagen), via rapid, apoptosis-driven organ involution (catagen) to a stage of relative "resting" (telogen). The controls that underlie these transformations clearly reside in and/or around the HF itself, and are likely to reflect - essentially autonomous, yet highly manipulable - changes in the local signalling milieu of e.g., hair growth-modulatory growth factors, cytokines, hormones and adhesion molecules. Yet the molecular nature and organization of the "hair cycle clock" (HCC) that drives these cyclic switches in the local signalling milieu remain obscure, and there is not even a fully satisfactory theory of hair cycle control. Since deciphering of the HCC is of paramount clinical importance, and since corresponding working hypotheses are badly needed to guide the design of more incisive experiments that identify the elusive central "oscillator" mechanism behind the HCC, we discuss basic requirements any convincing HCC theory should meet. After arguing that at least four distinct timing devices underlie HF chronobiology ("morphogenesis clock", "cycling inducer", "desynchronizer", and the actual HCC), previously proposed HCC theories are briefly and critically reviewed. In the light of intriguing regulatory similarities between the HCC and the cell cycle machinery, we suggest here that the HCC may be driven by autonomous, cell cycle-coupled secretory activities of the HF mesenchyme, namely by changes in the G0/G1-associated secretion of "papilla morphogens" by dermal papilla fibroblasts. Hopefully, this provocative hypothesis will encourage the proposition of novel, comprehensive HCC theories.

Animals↗