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Mucosal Addressin Cell Adhesion Molecule 1 Plays an Unexpected Role in the Development of Mouse Guard Hair

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Mucosal Addressin Cell Adhesion Molecule 1 Plays an Unexpected Role in the Development of Mouse Guard Hair View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Mucosal Addressin Cell Adhesion Molecule 1 Plays an Unexpected Role in the Development of Mouse Guard Hair Eri Nishioka,*²1 Toshiyuki Tanaka,³ Hisahiro Yoshida,* Kazuyoshi Matsumura,* Satomi Nishikawa,*§ Asuka Naito,¶ Jun-ichiro Inoue,** Yoko Funasaka,² Masamitsu Ichihashi,² Masayuki Miyasaka,³ and Shin-Ichi Nishikawa*§ *Department of Molecular Genetics, Graduate School of Medicine, Kyoto University, Kyoto, Japan; ²Department of Dermatology, Kobe University School of Medicine, Kobe, Japan; ³Laboratory of Molecular and Cellular Recognition, Osaka University Graduate School of Medicine, Suita, Japan; §Center for Developmental Biology, RIKEN, Kobe, Japan; ¶Division of Oncology, Institute of Medical Science, University of Tokyo, Tokyo, Japan; **Department of Applied Chemistry, Faculty of Science and Technology, Keio University, Yokohama, Japan The ®rst wave of coat hair development is initiated follicle development before involvement of Sonic around embryonic day 14 in the mouse. Whereas hedgehog signal. Follicle development in this culture ectodysplasin and ectodermal dysplasia receptor, was also suppressed to some extent, though not tumor necrosis factor and tumor necrosis factor completely, by addition of soluble mucosal addressin receptor family molecules, respectively, were identi- cell adhesion molecule 1/IgG-Fc chimeric protein, ®ed to be signals triggering this process, not much whereas monoclonal antibody that can inhibit muco- was known regarding their downstream molecular sal addressin cell adhesion molecule 1 interaction targets. In this report, we show that mucosal addres- with integrin a4b7 had no effect on this process. sin cell adhesion molecule 1 and intercellular adhe- These results demonstrated for the ®rst time that the sion molecule 1 are induced in the keratinocytes structural proteins, mucosal addressin cell adhesion of the hair placode as a direct consequence of ecto- molecule 1 and intercellular adhesion molecule 1, are dermal dysplasia receptor signal, and tumor-necro- induced by ectodermal dysplasia receptor signal and sis-factor-receptor-associated factor 6 is involved in suggested the potential involvement of mucosal this mucosal addressin cell adhesion molecule 1 addressin cell adhesion molecule 1 in the morpho- expression. Experiments using an in vitro culture of genesis of follicular keratinocytes. Key words: Edar/ skin fragments demonstrated that ectodermal-dyspla- hypohidrotic ectodermal dysplasia/keratinocyte/tumor necro- sia-receptor-induced mucosal addressin cell adhesion sis factor. J Invest Dermatol 119:632±638, 2002 molecule 1 expression occurs at the initial phase of t is well established that mammalian hair follicle and avian genetic proteins are involved in the initial process, as positive and feather formation are regulated by a set of signals such as negative regulators, respectively (Song et al, 1996; Jung et al, 1998), bone morphogenetic proteins, Sonic hedgehog (Shh), followed by a subsequent fate speci®cation process involving ®broblast growth factors (FGFs), Wnt, and Notch that Notch/Delta signals (Artavanis-Tsakonas and Simpson, 1991; Iappear successively during organogenesis of hair follicles as Crowe et al, 1998). Likewise, Notch has been implicated in hair well as that of other organs (for reviews see Oro and Scott, 1998; placode development (Powell et al, 1998). Recent studies showed Barsh, 1999). From histologic observations, it was proposed that that conditional deletion of the b-catenin gene from the epidermis hair follicle formation is initiated when underlying mesenchymal resulted in defects in the formation of the hair placode (Huelsken cells trigger commitment of the overlying epidermis to form the et al, 2001). Moreover, mice lacking the LEF-1 gene displayed placodes (Hardy, 1992; Oro and Scott, 1998). Concerning feather reduction in coat hair number and complete lack of whiskers (van development, it has been shown that FGFs and bone morpho- Genderen et al, 1994). As b-catenin and LEF-1 have been implicated downstream of Wnt signaling, these results indicate a Manuscript received March 20, 2002; accepted for publication May 7, role for Wnt signals in the initial phase of hair follicle development. 2002. Shh, another important signal that is involved repeatedly in many Reprint requests to: Dr. Eri Nishioka, Center for Developmental organogenesis processes (Ekker et al, 1995; Hardy et al, 1995; Biology, RIKEN, 2-2-3 Mnatojima Minamimachi, Chuo-Ku, Kobe, 650- Tanabe et al, 1995), is implicated in the subsequent processes of hair 0047, Japan. Email: [email protected] follicle development after placode formation, particularly in Abbreviations: E, embryonic day; Eda, ectodysplasin; EDA, anhidrotic elongation (St-Jacques et al, 1998; Chiang et al, 1999). Despite ectodermal dysplasia; Edar, ectodermal dysplasia receptor; HED, hypohi- this increasing list of molecules regulating hair follicle development, drotic ectodermal dysplasia; IkB, inhibitor of NF-kB; IKK, IkB kinase; the nature of the initiating signal has remained elusive. MAdCAM, mucosal addressin cell adhesion molecule; NF-kB, nuclear factor kB; TNFR, TNF receptor; TRAF, TNFR-associated factor; Shh, Hypohidrotic (anhidrotic) ectodermal dysplasia [HED (EDA)] Sonic hedgehog; Xedar, X-linked EDA-A2 receptor. stands for a syndrome characterized by hypoplastic development in 1Present address: Center for Developmental Biology, RIKEN, Kobe, ectodermal organs including teeth, hair, and sweat glands and is Japan. composed of X-linked, autosomal recessive and variant forms. After 0022-202X/02/$15.00 ´ Copyright # 2002 by The Society for Investigative Dermatology, Inc. 632 VOL. 119, NO. 3 SEPTEMBER 2002 MAdCAM-1 EXPRESSION IN MOUSE HAIR DEVELOPMENT 633 the identi®cation of the gene responsible for X-linked HED (Kere Skin organ culture The organ culture system was adapted from et al, 1996), called EDA, the corresponding mouse gene was cloned Kashiwagi et al (1997). In brief, skin specimens were prepared from the and found to be allelic to the tabby (Ta) locus (Srivastava et al, dorsal coat of E13±13.5 embryos and spread epidermal side up onto a 1997). From the deduced amino acid sequence, the Ta protein and Nuclepore polycarbonate Track Etch Membrane (Nuclepore Europe, Whatman International, U.K.) coated with growth factor reduced EDA product, ectodysplasin (Eda), were identi®ed as tumor Matrigel (Becton Dickinson Biosciences, Bedford, MA). The tissue necrosis factor (TNF) family members (Ezer et al, 1999; Mikkola pieces were incubated at the air±liquid interface, ¯oating on 2 ml of et al, 1999). In complete agreement with this, subsequent cloning of Dulbecco's modi®ed Eagle's medium (Gibco BRL, Grand Island, NY) the gene responsible for downless (dL), which shares a phenotype supplemented with 1% fetal bovine serum, 50 U per ml penicillin, and identical to tabby mice, revealed that the dL gene encodes a novel 50 mg per ml streptomycin, in 35 mm plastic culture dishes with 5% TNF receptor (TNFR) called Edar (for ectodermal dysplasia CO2 at 37°C. EGF, cyclopamine, MAdCAM-1-Ig, and human IgG-Fc receptor) (Headon and Overbeek, 1999). The tabby and downless were added directly to the culture medium. mice (Eda-null and Edar-null mice, respectively) lack primary coat Histology and immunohistochemistry For whole-mount immuno- hair follicles (called guard hair or monotrich) and sweat glands and staining, the embryos and organ culture explants were ®xed in 2% exhibit teeth abnormalities. As the human homolog of dL was paraformaldehyde (pH 7.4) (microwaved for 20 s at 600 W and kept on shown to be mutated in patients with an autosomal recessive form ice for 30 min), and then processed as previously described (Adachi et al, of HED (Monreal et al, 1999), whose phenotype is indistinguish- 1997). In brief, specimens were washed in phosphate-buffered saline (PBS) after ®xation, serially dehydrated with methanol, blocked for able from X-linked HED, this suggested that Eda and Edar might intrinsic peroxidase activities in 0.3% H2O2, and rehydrated. After act as a ligand and a receptor, respectively, in hair development. incubation with PBS-MT (1% skim milk, 0.1% Triton X-100 in PBS) to Eda and Edar were shown to interact in vitro (Tucker et al, 2000; inhibit nonspeci®c binding, specimens were incubated with primary Yan et al, 2000) and subsequent studies investigating the relation- antibodies overnight and washed in PBS-T (0.1% Triton X-100 in PBS). ship between this and other factors strongly suggested Eda/Edar to After incubation with horseradish peroxidase (HRP) conjugated be the most upstream signal in hair follicle development (Huelsken secondary reagents, color reactions were carried out with et al, 2001). diaminobenzidine and nickel chloride. Stained explants and embryos TNF family molecules have been studied most extensively in the were embedded in polyesterwax and sections (7 mm) were counterstained with hematoxylin and eosin as needed. For cryosections used for context of in¯ammation and lympho-hematopoietic organogenesis. immunostaining, embryos ®xed in 2% paraformaldehyde were washed in In these settings, the most common outcome induced by this class PBS, embedded in OCT compound, and then snap frozen in liquid of signals is expression of cell adhesion molecules (CAM). TNF and nitrogen. Cryostat sections (7±10 mm) were washed in PBS and intrinsic lymphotoxin have been shown to induce expression of
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