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• W2116722953 abstract "Ectodysplasin (Eda) and its receptor (Edar) are required for normal development of several ectodermal derivatives including hair follicles (HFs). Here, we show that during the murine hair cycle the expression of Eda A1, Edar, Edaradd, and TRAF6 transcripts are minimal in the resting phase and maximal during HF transition from active growth to regression (catagen). Eda A1 mRNA and Edar proteins were expressed in the hair matrix and outer and inner root sheaths of anagen HFs. During catagen, Eda A1 mRNA and Edar protein were expressed in the outer and inner root sheaths and later in the secondary hair germ. Catagen development accompanied by increased apoptosis in the outer root sheath was significantly accelerated in downless mice or after treatment of wild-type mice by a fusion protein that inhibits Edar signaling, compared with the corresponding controls. Microarray, real-time polymerase chain reaction, and immunohistochemical analyses of skin of downless mice revealed a strong decrease of expression of X-linked inhibitor of apoptosis protein (XIAP), compared with the controls, suggesting XIAP as a target for Edar signaling. Thus, our data demonstrate that in addition to its well-established role in HF morphogenesis, Edar signaling is also involved in hair cycle control and regulates apoptosis in HF keratinocytes during catagen. Ectodysplasin (Eda) and its receptor (Edar) are required for normal development of several ectodermal derivatives including hair follicles (HFs). Here, we show that during the murine hair cycle the expression of Eda A1, Edar, Edaradd, and TRAF6 transcripts are minimal in the resting phase and maximal during HF transition from active growth to regression (catagen). Eda A1 mRNA and Edar proteins were expressed in the hair matrix and outer and inner root sheaths of anagen HFs. During catagen, Eda A1 mRNA and Edar protein were expressed in the outer and inner root sheaths and later in the secondary hair germ. Catagen development accompanied by increased apoptosis in the outer root sheath was significantly accelerated in downless mice or after treatment of wild-type mice by a fusion protein that inhibits Edar signaling, compared with the corresponding controls. Microarray, real-time polymerase chain reaction, and immunohistochemical analyses of skin of downless mice revealed a strong decrease of expression of X-linked inhibitor of apoptosis protein (XIAP), compared with the controls, suggesting XIAP as a target for Edar signaling. Thus, our data demonstrate that in addition to its well-established role in HF morphogenesis, Edar signaling is also involved in hair cycle control and regulates apoptosis in HF keratinocytes during catagen. The hair follicle (HF) is a skin appendage that develops as a result of epithelial-mesenchymal interactions between epidermal keratinocytes committed to hair-specific differentiation and a cluster of dermal fibroblasts that forms the follicular papilla.1Hardy MH The secret life of the hair follicle.Trends Genet. 1992; 8: 55-61Abstract Full Text PDF PubMed Scopus (813) Google Scholar, 2Fuchs E Raghavan S Getting under the skin of epidermal morphogenesis.Nat Rev Genet. 2002; 3: 199-209Crossref PubMed Scopus (584) Google Scholar, 3Millar SE Molecular mechanisms regulating hair follicle development.J Invest Dermatol. 2002; 118: 216-225Crossref PubMed Scopus (724) Google Scholar, 4Botchkarev VA Paus R Molecular biology of hair morphogenesis: development and cycling.J Exp Zoolog B Mol Dev Evol. 2003; 298: 164-180Crossref PubMed Scopus (131) Google Scholar, 5Schmidt-Ullrich R Paus R Molecular principles of hair follicle induction and morphogenesis.Bioessays. 2005; 27: 247-261Crossref PubMed Scopus (398) Google Scholar During postnatal life, HFs show patterns of cyclic activity with periods of active growth and hair production (anagen), apoptosis-driven involution (catagen), and relative resting/hair shedding (telogen/exogen).6Fuchs E Merrill BJ Jamora C DasGupta R At the roots of a never-ending cycle.Dev Cell. 2001; 1: 13-25Abstract Full Text Full Text PDF PubMed Scopus (235) Google Scholar, 7Stenn KS Paus R Control of hair follicle cycling.Physiol Rev. 2001; 81: 449-494Crossref PubMed Scopus (1133) Google Scholar, 8Botchkarev VA Kishimoto J Molecular control of epithelial-mesenchymal interactions during hair follicle cycling.J Investig Dermatol Symp Proc. 2003; 8: 46-55Abstract Full Text Full Text PDF PubMed Scopus (243) Google Scholar HF development and cycling are controlled by similar signaling networks within and between the follicular epithelium and mesenchyme, using the molecules that belong to the bone morphogenetic protein (BMP)/transforming growth factor (TGF)-β, epidermal growth factor, fibroblast growth factor, Hedgehog, insulin-like growth factor, Notch, neurotrophin, tumor necrosis factor, and Wnt families.5Schmidt-Ullrich R Paus R Molecular principles of hair follicle induction and morphogenesis.Bioessays. 2005; 27: 247-261Crossref PubMed Scopus (398) Google Scholar, 6Fuchs E Merrill BJ Jamora C DasGupta R At the roots of a never-ending cycle.Dev Cell. 2001; 1: 13-25Abstract Full Text Full Text PDF PubMed Scopus (235) Google Scholar, 8Botchkarev VA Kishimoto J Molecular control of epithelial-mesenchymal interactions during hair follicle cycling.J Investig Dermatol Symp Proc. 2003; 8: 46-55Abstract Full Text Full Text PDF PubMed Scopus (243) Google Scholar, 9Dlugosz AA The Hedgehog and the hair follicle: a growing relationship.J Clin Invest. 1999; 104: 851-853Crossref PubMed Scopus (26) Google Scholar, 10Callahan CA Oro AE Monstrous attempts at adnexogenesis: regulating hair follicle progenitors through Sonic hedgehog signaling.Curr Opin Genet Dev. 2001; 11: 541-546Crossref PubMed Scopus (62) Google Scholar, 11Cotsarelis G Millar SE Towards a molecular understanding of hair loss and its treatment.Trends Mol Med. 2001; 7: 293-301Abstract Full Text Full Text PDF PubMed Scopus (223) Google Scholar, 12Millar S An ideal society? Neighbors of diverse origins interact to create and maintain complex mini-organs in the skin.PLOS Biol. 2005; 3: e372Crossref PubMed Scopus (17) Google Scholar Ectodysplasin receptor (Edar) and two other structurally similar receptors Xedar and Troy are members of the tumor necrosis factor receptor superfamily that signals predominantly via the nuclear factor (NF)-κB transcription factors.13Mikkola ML Thesleff I Ectodysplasin signaling in development.Cytokine Growth Factor Rev. 2003; 14: 211-224Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar Edar ligand Eda A1, a product of the Ectodysplasin (Eda) gene, differs from the Xedar ligand Eda A2 by the presence of only two additional amino acids in the tumor necrosis factor motif.14Bayés M Hartung AJ Ezer S Pispa J Thesleff I Srivastava AK Kere J The anhidrotic ectodermal dysplasia gene (EDA) undergoes alternative splicing and encodes ectodysplasin-A with deletion mutations in collagenous repeats.Hum Mol Genet. 1998; 7: 1661-1669Crossref PubMed Scopus (185) Google Scholar, 15Yan M Wang LC Hymowitz SG Schilbach S Lee J Goddard A de Vos AM Gao WQ Dixit VM Two-amino acid molecular switch in an epithelial morphogen that regulates binding to two distinct receptors.Science. 2000; 290: 523-527Crossref PubMed Scopus (243) Google Scholar, 16Hymowitz SG Compaan DM Yan M Wallweber HJ Dixit VM Starovasnik MA de Vos AM The crystal structures of EDA-A1 and EDA-A2: splice variants with distinct receptor specificity.Structure. 2003; 11: 1513-1520Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar Despite these minor structural differences, Eda A1 and Eda A2 show very high specificity to their corresponding receptors Edar and Xedar.15Yan M Wang LC Hymowitz SG Schilbach S Lee J Goddard A de Vos AM Gao WQ Dixit VM Two-amino acid molecular switch in an epithelial morphogen that regulates binding to two distinct receptors.Science. 2000; 290: 523-527Crossref PubMed Scopus (243) Google Scholar, 16Hymowitz SG Compaan DM Yan M Wallweber HJ Dixit VM Starovasnik MA de Vos AM The crystal structures of EDA-A1 and EDA-A2: splice variants with distinct receptor specificity.Structure. 2003; 11: 1513-1520Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar Eda A1 binding to Edar results in the recruitment of the auxiliary protein Edaradd, which binds the selected TRAF proteins (TRAF1/2/3 and 5/6).15Yan M Wang LC Hymowitz SG Schilbach S Lee J Goddard A de Vos AM Gao WQ Dixit VM Two-amino acid molecular switch in an epithelial morphogen that regulates binding to two distinct receptors.Science. 2000; 290: 523-527Crossref PubMed Scopus (243) Google Scholar, 17Headon DJ Emmal SA Ferguson BM Tucker AS Justice MJ Sharpe PT Zonana J Overbeek PA Gene defect in ectodermal dysplasia implicates a death domain adapter in development.Nature. 2001; 414: 913-916Crossref PubMed Scopus (296) Google Scholar, 18Morlon A Munnich A Smahi A TAB2, TRAF6 and TAK1 are involved in NF-kappaB activation induced by the TNF-receptor, Edar and its adaptator Edaradd.Hum Mol Genet. 2005; 14: 3751-3757Crossref PubMed Scopus (77) Google Scholar TAB2 is an adaptator protein that bridges TRAF6 to TAK1 (TGF-β-activated kinase 1), allowing TAK1 activation and subsequent activation of NF-κB transcription factors, their translocation into the nucleus, and modulation of the activity of the corresponding target genes.18Morlon A Munnich A Smahi A TAB2, TRAF6 and TAK1 are involved in NF-kappaB activation induced by the TNF-receptor, Edar and its adaptator Edaradd.Hum Mol Genet. 2005; 14: 3751-3757Crossref PubMed Scopus (77) Google Scholar, 19Smahi A Courtois G Rabia SH Doffinger R Bodemer C Munnich A Casanova JL Israel A The NF-kappaB signalling pathway in human diseases: from incontinentia pigmenti to ectodermal dysplasias and immune-deficiency syndromes.Hum Mol Genet. 2002; 11: 2371-2375Crossref PubMed Google Scholar Defects in the genes that encode proteins of the Edar signaling pathway cause hypohidrotic ectodermal dysplasias in humans and similar conditions in mice.20Drögemüller C Distl O Leeb T X-linked anhidrotic ectodermal dysplasia (ED1) in men, mice, and cattle.Genet Sel Evol. 2003; 35: S137-S145Crossref PubMed Google Scholar Hypohidrotic ectodermal dysplasia is characterized by severe defects in ectodermal appendage development, including hairs, teeth, and exocrine glands. In mice, hypohidrotic ectodermal dysplasia is caused by the defects in Eda (Tabby), Edar (Downless), Edarrad (Crinkled), and TRAF6 genes.17Headon DJ Emmal SA Ferguson BM Tucker AS Justice MJ Sharpe PT Zonana J Overbeek PA Gene defect in ectodermal dysplasia implicates a death domain adapter in development.Nature. 2001; 414: 913-916Crossref PubMed Scopus (296) Google Scholar, 21Ferguson BM Brockdorff N Formstone E Ngyuen T Kronmiller JE Zonana J Cloning of Tabby, the murine homolog of the human EDA gene: evidence for a membrane-associated protein with a short collagenous domain.Hum Mol Genet. 1997; 6: 1589-1594Crossref PubMed Scopus (146) Google Scholar, 22Headon DJ Overbeek PA Involvement of a novel TNF receptor homologue in hair follicle induction.Nat Genet. 1999; 22: 370-374Crossref PubMed Scopus (312) Google Scholar, 23Naito A Yoshida H Nishioka E Satoh M Azuma S Yamamoto T Nishikawa S-I Inoue J-I TRAF6-deficient mice display hypohidrotic ectodermal dysplasia.Proc Natl Acad Sci USA. 2002; 99: 8766-8771Crossref PubMed Scopus (151) Google Scholar Hair phenotypes seen in these mice include the absence of the guard and zig-zag hairs and presence of two intermediate hair types (awl and auchene), which show lack of normal arrangement of the air cells in the hair medulla.24Kindred B The expression of Tabby and Crinkled genes in different genetic backgrounds in the mouse.Genetics. 1967; 55: 173-178PubMed Google Scholar, 25Sundberg JP Hogan ME Hair types and subtypes in the laboratory mouse.in: Sundberg JP Handbook of Mouse Mutations with Skin and Hair Abnormalities: Animal Models and Biomedical Tools. CRC Press, Boca Raton, FL1994: 57-68Google Scholar In contrast to Edar deficiency, genetic Xedar ablation is not accompanied by any visible skin or HF abnormalities.26Newton K French DM Yan M Frantz GD Dixit VM Myodegeneration in EDA-A2 transgenic mice is prevented by XEDAR deficiency.Mol Biol Cell. 2004; 24: 1608-1613Crossref Scopus (60) Google Scholar A critical role for Edar pathway in the molecular signaling network that regulates HF development is also evident from the facts that gain of Edar signaling leads to partial rescue of the Tabby phenotype and also alters cell fate in the epidermis. In particular, it was shown that pharmacological administration of soluble Eda A1-Fc chimeric protein to pregnant Tabby mice or overexpression of Eda A1 under control of the CMV promoter on Tabby background result in the appearance of guard HFs, tail hairs, and exocrine glands.27Gaide O Schneider P Permanent correction of an inherited ectodermal dysplasia with recombinant EDA.Nat Med. 2003; 9: 614-618Crossref PubMed Scopus (170) Google Scholar, 28Srivastava AK Durmowicz MC Hartung AJ Hudson J Ouzts LV Donovan DM Cui CY Schlessinger D Ectodysplasin-A1 is sufficient to rescue both hair growth and sweat glands in Tabby mice.Hum Mol Genet. 2001; 10: 2973-2981Crossref PubMed Scopus (82) Google Scholar, 29Cui CY Durmowicz M Ottolenghi C Hashimoto T Griggs B Srivastava AK Schlessinger D Inducible mEDA-A1 transgene mediates sebaceous gland hyperplasia and differential formation of two types of mouse hair follicles.Hum Mol Genet. 2003; 12: 2931-2940Crossref PubMed Scopus (59) Google Scholar However, neither Eda A1-Fc treatment nor transgenic expression of Eda A1 resulted in the appearance of zig-zag hairs in Tabby mice.27Gaide O Schneider P Permanent correction of an inherited ectodermal dysplasia with recombinant EDA.Nat Med. 2003; 9: 614-618Crossref PubMed Scopus (170) Google Scholar Gain of the Eda A1 levels in the epidermis of transgenic mice (promoters: K14 or involucrin) also results in alterations in the HF patterning and formation of fused HFs because of the loss of proper spacing between neighboring HFs.30Mustonen T Ilmonen M Pummila M Kangas AT Laurikkala J Jaatinen R Pispa J Gaide O Schneider P Thesleff I Mikkola ML Ectodysplasin A1 promotes placodal cell fate during early morphogenesis of ectodermal appendages.Development. 2004; 131: 4907-4919Crossref PubMed Scopus (130) Google Scholar, 31Zhang M Brancaccio A Weiner L Missero C Brissette JL Ectodysplasin regulates pattern formation in the mammalian hair coat.Genesis. 2003; 37: 30-37Crossref PubMed Scopus (24) Google Scholar Fused HFs are joined together at their permanent portions by the outer epithelial layers, and within a fusion, each individual HF possesses its own hair bulb, dermal papilla, hair shaft, and sebaceous gland.30Mustonen T Ilmonen M Pummila M Kangas AT Laurikkala J Jaatinen R Pispa J Gaide O Schneider P Thesleff I Mikkola ML Ectodysplasin A1 promotes placodal cell fate during early morphogenesis of ectodermal appendages.Development. 2004; 131: 4907-4919Crossref PubMed Scopus (130) Google Scholar, 31Zhang M Brancaccio A Weiner L Missero C Brissette JL Ectodysplasin regulates pattern formation in the mammalian hair coat.Genesis. 2003; 37: 30-37Crossref PubMed Scopus (24) Google Scholar In addition, some K14-Eda A1 mice show formation of only curly hairs, whereas others have only straight hairs that resemble guard and awl hairs seen in wild-type mice.32Mustonen T Pispa J Mikkola ML Pummila M Kangas AT Pakkasjarvi L Jaatinen R Thesleff I Stimulation of ectodermal organ development by ectodysplasin-A1.Dev Biol. 2003; 259: 123-136Crossref PubMed Scopus (215) Google Scholar In Inv-Eda A1 transgenic mice, guard, awl, and auchene hairs look normal, whereas zig-zag hairs are replaced by curly hairs that show a single column of air cells in the medulla.31Zhang M Brancaccio A Weiner L Missero C Brissette JL Ectodysplasin regulates pattern formation in the mammalian hair coat.Genesis. 2003; 37: 30-37Crossref PubMed Scopus (24) Google Scholar However, little is known about the involvement of Edar signaling in the control of postnatal HF cycling. It was shown that in K14-Eda A1 transgenic mice, the first anagen is prolonged,32Mustonen T Pispa J Mikkola ML Pummila M Kangas AT Pakkasjarvi L Jaatinen R Thesleff I Stimulation of ectodermal organ development by ectodysplasin-A1.Dev Biol. 2003; 259: 123-136Crossref PubMed Scopus (215) Google Scholar suggesting that Edar signaling could play a role in postnatal hair cycle control in addition to its well-established role in HF morphogenesis. To explore this hypothesis, we demonstrate here that the expression of the components of Edar signaling pathways in mouse skin fluctuate in a hair cycle-dependent manner and reach their maximum during the late anagen-early catagen phases. We also show that genetic loss or pharmacological inhibition of Edar signaling results in significant catagen acceleration. Furthermore, we demonstrate that Edar deletion is accompanied by a significant decrease in the expression of X-linked inhibitor of apoptosis protein (XIAP) in skin and HFs, suggesting XIAP as a target of Edar signaling. Thus, our data demonstrate that Edar signaling interferes with the cyclic regeneration of postnatal HFs at least in part by regulating apoptosis during catagen. Eight-week-old C57BL/6J and FVB mice were purchased from Charles River (Wilmington, MA) and housed in the community cages at the Laboratory Animal Science Center of the Boston University School of Medicine. Downless (dl) mice were kindly provided by Prof. P. Overbeek (Baylor College of Medicine, Houston, TX). All mice were fed water and murine chow ad libitum and kept under 12-hour light/dark cycles. Active hair growth (anagen) was induced in the back skin during telogen phase of the hair cycle by depilation as previously described.33Müller-Röver S Handjiski B van der Veen C Eichmuller S Foitzik K McKay IA Stenn KS Paus R A comprehensive guide for the accurate classification of murine hair follicles in distinct hair cycle stages.J Invest Dermatol. 2001; 117: 3-15Crossref PubMed Google Scholar Skin samples were harvested at distinct hair cycle stages (telogen, anagen II, IV, and VI, catagen II to VI; days 0, 3, 5, 12, 16, and 18 after depilation, respectively; three to five animals per stage). After harvesting, skin samples were processed for biochemical or immunohistochemical studies, as described below. For immunohistochemical studies, the back skin was harvested parallel to the vertebral line and was embedded for subsequently obtaining longitudinal cryosections through the HF.33Müller-Röver S Handjiski B van der Veen C Eichmuller S Foitzik K McKay IA Stenn KS Paus R A comprehensive guide for the accurate classification of murine hair follicles in distinct hair cycle stages.J Invest Dermatol. 2001; 117: 3-15Crossref PubMed Google Scholar RNA was isolated from the snap-frozen skin samples using Trizol reagent (Invitrogen, Carlsbad, CA), followed by DNase I treatment and purification on RNeasy columns (Qiagen, Carlsbad, CA). Two μg of each RNA sample were converted to first strand cDNA using a first strand cDNA synthesis kit (Amersham, Piscataway, NJ). The resulting cDNAs were amplified with Eda A1-, Edar-, Edaradd-, TRAF6-, and HPRT-specific primers (Table 1) using Taq polymerase under the following cycling conditions: 94°C for 3 minutes, followed by denaturing at 94°C for 30 seconds, annealing at 56 to 65°C for 15 seconds, and amplification at 72°C for 30 seconds, repeated for 36 to 40 cycles. RNA dilutions without reverse transcription reaction were included as controls. The PCR products were analyzed by standard agarose gel electrophoresis with ethidium bromide staining. RNA samples from at least two different animals were used for each experimental condition with similar results.Table 1PCR PrimerscDNAForward primerReverse primerEda A15′-ATTCCAGGAACAACTGTTATG-3′5′-AAGTTGATGTAGTAGACTTC-3′Edar5′-ACCAGGAGATGGAAAA-3′5′-GCTGGATGAGTGTGCTGA-3′Edaradd5′-ATTACCACGCAAGAGGTTGG-3′5′-TCTCCCTGAGGTTGGTCATC-3′TRAF65′-CTTAGCTGCTGGGGTGTCTC-3′5′-TCTCCAGAGGTGGGTCAAAC-3′HPRT5′-CTTTCCCTGGTTAAGCAGTACAG-3′5′-CATATCCAACAACAAACTTGTCTGG-3′XIAP5′-TGGACTCTACTACACAGGTATTGG-3′5′-AACTCACAGCATCAGATTCACTTC-3′ Open table in a new tab For microarray analysis, 5 μg of RNA isolated from full-thickness dl or control FVB mouse skin collected on days 16 to 17 after depilation was converted into 32P-labeled probes using Ampo-Labeling-LPR kit (SuperArray Bioscience, Frederick, MD). The probes were used for microarray analysis using the Mouse Apoptosis GEArrays kit (SuperArray Bioscience, Frederick, MD; http://www.superarray.com). The resulting filters were analyzed using Cyclone Phosphor System (Perkin-Elmer Life Sciences, Boston, MA). For real-time reverse transcriptase (RT)-PCR, 1 μg of each RNA sample from dl or FVB mouse skin collected on days 16 to 17 after depilation was used as a template for cDNA synthesis using SuperScript III first-strand synthesis system and poly dT primer (InVitrogene, San Diego, CA). PCR primers were designed on Beacon Designer software (Premier Biosoft Int., Palo Alto, CA; Table 1). PCR was performed using the iCycler thermal cycler (Bio-Rad Corp., Hercules, CA), as described previously.34Mammucari C Tommasi di Vignano A Sharov AA Neilson J Havrda MC Roop DR Botchkarev VA Crabtree GR Dotto GP Integration of Notch 1 and calcineurin/NFAT signaling pathways in keratinocyte growth and differentiation control.Dev Cell. 2005; 8: 665-676Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar Real-time PCR was performed using iQ SYBR green supermix and MyiQ single-color real-time PCR detection system (Bio-Rad Corp.). Differences between samples and controls were calculated using the Gene Expression Macro program (Bio-Rad Corp.) based on the ΔΔCt equitation method and normalized to the corresponding GAPDH values, as described before.34Mammucari C Tommasi di Vignano A Sharov AA Neilson J Havrda MC Roop DR Botchkarev VA Crabtree GR Dotto GP Integration of Notch 1 and calcineurin/NFAT signaling pathways in keratinocyte growth and differentiation control.Dev Cell. 2005; 8: 665-676Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar Total tissue proteins obtained from full thickness back skin extracts of mice on days 0, 12, and 18 after depilation were collected in lysis buffer, and protein concentrations were determined as described previously.34Mammucari C Tommasi di Vignano A Sharov AA Neilson J Havrda MC Roop DR Botchkarev VA Crabtree GR Dotto GP Integration of Notch 1 and calcineurin/NFAT signaling pathways in keratinocyte growth and differentiation control.Dev Cell. 2005; 8: 665-676Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar Western analysis was performed with goat polyclonal anti-Edar antiserum (R&D Systems, Minneapolis, MN). For control of specificity, protein lysates from the anagen mouse skin (12 days after depilation) were analyzed with anti-Edar antiserum preincubated with Edar-Fc protein (2 μg/ml; R&D Systems) for 2 hours at 37°C. Horseradish peroxidase-tagged donkey anti-goat IgG was used as secondary antibody (Santa Cruz Biotechnology, Santa Cruz, CA). In situ hybridization using Dig-labeled anti-sense riboprobe for Eda spanning nucleotides 161 to 1997 of Eda cDNA (gift of Dr. I. Thesleff, Institute of Biotechnology, University of Helsinki, Finland) was performed as previously described.35Botchkarev VA Botchkareva NV Roth W Nakamura M Chen L-H Herzog W Lindner G McMahon JA Peters C Lauster R McMahon AP Paus R Noggin is a mesenchymally-derived stimulator of hair follicle induction.Nat Cell Biol. 1999; 1: 158-164Crossref PubMed Scopus (336) Google Scholar, 36Botchkarev VA Botchkareva NV Nakamura M Huber O Funa K Lauster R Paus R Gilchrest BA Noggin is required for induction of the hair follicle growth phase in postnatal skin.FASEB J. 2001; 15: 2205-2214Crossref PubMed Scopus (183) Google Scholar Immunofluorescent detection of Edar, Fc-fragment of human IgG1, Shh, activated caspase 3, and XIAP was performed using the corresponding primary antisera (R&D Systems, and Jackson ImmunoResearch Laboratories, West Grove, PA) according to the protocols described previously.37Sharov AA Weiner L Sharova TY Siebenhaar F Atoyan R McNamara CA Funa K Gilchrest BA Brissette JL Botchkarev VA Noggin overexpression inhibits eyelid opening by altering epidermal apoptosis and differentiation.EMBO J. 2003; 22: 2992-3003Crossref PubMed Scopus (64) Google Scholar, 38Sharov AA Fessing MY Atoyan R Sharova TY Haskell-Luevano C Weiner L Funa K Brissette JL Gilchrest BA Botchkarev VA Bone morphogenetic protein (BMP) signaling controls hair pigmentation by means of cross-talk with the melanocortin receptor-1 pathway.Proc Natl Acad Sci USA. 2005; 102: 93-98Crossref PubMed Scopus (59) Google Scholar For analyses of apoptotic cells, terminal dUTP nick-end labeling (TUNEL) staining was performed, as described elsewhere.39Lindner G Botchkarev VA Botchkareva NV Ling G van der Veen C Paus R Analysis of apoptosis during hair follicle regression (catagen).Am J Pathol. 1997; 151: 1601-1617PubMed Google Scholar, 40Botchkarev VA Komarova EV Siebenhaar F Botchkareva NV Komarov PG Maurer M Gilchrest BA Gudkov AV p53 is essential for chemotherapy-induced hair loss.Cancer Res. 2000; 60: 5002-5006PubMed Google Scholar, 41Sharov AA Li GZ Palkina TN Sharova TY Gilchrest BA Botchkarev VA Fas and c-kit are involved in the control of hair follicle melanocyte apoptosis and migration in chemotherapy-induced hair loss.J Invest Dermatol. 2003; 120: 27-35Crossref PubMed Scopus (49) Google Scholar, 42Sharov AA Siebenhaar F Sharova TY Botchkareva NV Gilchrest BA Botchkarev VA Fas signaling is involved in the control of hair follicle response to chemotherapy.Cancer Res. 2004; 64: 6266-6270Crossref PubMed Scopus (30) Google Scholar For morphological analyses of the HFs, frozen sections of the mouse skin were stained for alkaline phosphatase activity as previously described.33Müller-Röver S Handjiski B van der Veen C Eichmuller S Foitzik K McKay IA Stenn KS Paus R A comprehensive guide for the accurate classification of murine hair follicles in distinct hair cycle stages.J Invest Dermatol. 2001; 117: 3-15Crossref PubMed Google Scholar To inhibit the Edar signaling in postnatal murine skin, recombinant mouse Edar protein fused with the Fc-fragment of human IgG (Edar-Fc; R&D Systems) or Fc-fragment of human IgG1 (Fc-IgG) as a control was administered into the skin of 12-week-old C57BL/6J mice. Four μg of Edar-Fc or 2.5 μg of Fc-IgG were injected subcutaneously to each animal once a day starting on days 10 or 14 after depilation and skin samples were collected on days 18 to 19 after depilation. At least three animals of each strain were used for every experimental condition, and the obtained results were essentially identical in all animals. Immunoreactivity patterns were scrutinized by studying at least 50 different HFs per mouse, and five mice were assessed per hair cycle stage. The percentage of HFs at distinct catagen stages was assessed and compared between dl and wild-type mice at P14.5 to P17.5, as well as between mice treated by Edar-Fc or Fc-IgG. All evaluations were performed on the basis of accepted morphological criteria of HF classification.33Müller-Röver S Handjiski B van der Veen C Eichmuller S Foitzik K McKay IA Stenn KS Paus R A comprehensive guide for the accurate classification of murine hair follicles in distinct hair cycle stages.J Invest Dermatol. 2001; 117: 3-15Crossref PubMed Google Scholar Only every 10th cryosection was used for analysis to exclude the repetitive evaluation of the same HF, and two to three cryosections were assessed from each animal. Altogether, 250 to 300 HFs in 50 to 60 microscopic fields, derived from six animals of the experimental group (∼40 to 50 follicles per animal) were analyzed and compared with those with corresponding numbers of HFs from the control mice. The number of TUNEL-positive cells was assessed in the hair matrix, outer and inner root sheaths of catagen II to III HFs in dl mice, Edar-Fc-treated mice, and corresponding controls as described previously.41Sharov AA Li GZ Palkina TN Sharova TY Gilchrest BA Botchkarev VA Fas and c-kit are involved in the control of hair follicle melanocyte apoptosis and migration in chemotherapy-induced hair loss.J Invest Dermatol. 2003; 120: 27-35Crossref PubMed Scopus (49) Google Scholar, 42Sharov AA Siebenhaar F Sharova TY Botchkareva NV Gilchrest BA Botchkarev VA Fas signaling is involved in the control of hair follicle response to chemotherapy.Cancer Res. 2004; 64: 6266-6270Crossref PubMed Scopus (30) Google Scholar, 43Botchkarev VA Botchkareva NV Albers KM Chen L-H Welker P Paus R A role for p75 neurotrophin receptor in the control of apoptosis-driven hair follicle regression.FASEB J. 2000; 14: 1931-1942Crossref PubMed Scopus (83) Google Scholar, 44Botchkarev VA Komarova EA Siebenhaar F Botchkareva NV Maurer M Gudkov AV Gilchrest BA p53 involvement in the control of murine hair follicle regression.Am J Pathol. 2001; 158: 1913-1919Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar In total, 40 to 50 such measurements were performed in 50 to 60 microscopic fields derived from three animals per experimental and control group. All sections were analyzed at ×200 to ×400 magnifications, and means and SEM were calculated from the pooled data. Differences were judged as significant if the P value was lower than 0.05, as determined by the independent Student's t-test for unpaired samples. To obtain the first clues about a possible role of Edar signaling in postnatal hair cycling, we analyzed the expression of the components of the Edar pathway in normal mouse back skin during the depilation-induced hair cycle by semiquantita" @default.
• W2116722953 created "2016-06-24" @default.
• W2116722953 creator A5003961897 @default.
• W2116722953 creator A5023981166 @default.
• W2116722953 creator A5065104224 @default.
• W2116722953 creator A5078703402 @default.
• W2116722953 creator A5090650222 @default.
• W2116722953 date "2006-12-01" @default.
• W2116722953 modified "2023-10-18" @default.
• W2116722953 title "Involvement of the Edar Signaling in the Control of Hair Follicle Involution (Catagen)" @default.
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