Ectodysplasin A

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Pascal Schneider - One of the best experts on this subject based on the ideXlab platform.

  • SchemAtic of the feAther pAtterning mechAnism in flighted birds.
    2019
    Co-Authors: Lucy Freem, Debiao Zhao, Kevin J. Painter, Thomas E. Woolley, Eamonn A. Gaffney, Michael J. Mcgrew, Athanasia Tzika, Michel C. Milinkovitch, Pascal Schneider
    Abstract:

    (A) A competent epidermis overlies A mesenchyme displAying high mesenchymAl cell density on the midline (dense dermis) And grAduAlly decreAsing to the sides (loose dermis). (B) A trAvelling wAve of EDA signAlling stimulAtes the epidermAl production of FGF20, which induces chemotAxis of mesenchymAl cells And thus formAtion of A dermAl condensAte. As the condensAte forms, FGF20 expression is further stimulAted, thereby reinforcing production of this AttrActAnt. The clustering of cells Also stimulAtes the production And secretion of BMP to inhibit FGF20 production, limiting the size of the incipient primordium And preventing fusions between neighbouring primordiA. MeAnwhile, the previously loose dermis increAses in density to reAch the threshold density thAt permits condensAte formAtion. (C) As the EDA signAlling wAve sweeps Across the skin, the reAction-diffusion-tAxis system is repeAted until the wAve terminAtes At the edge of the trActs. BMP, bone morphogenetic protein; EDA, EctodysplAsin A; FGF20, fibroblAst growth fActor 20.

  • Role of EctodysplAsin signAlling in middle eAr And nAsAl pAthology in rAt And mouse models of hypohidrotic ectodermAl dysplAsiA
    The Company of Biologists, 2019
    Co-Authors: Jorge Del-pozo, Pascal Schneider, Neil Macintyre, Ali Azar, Denis Headon, Michael Cheeseman
    Abstract:

    PAtients with mutAtions in the EctodysplAsin receptor signAlling pAthwAy genes – the X-linked ligAnd EctodysplAsin-A (EDA), the receptor EDAR or the receptor AdApter EDARADD – hAve hypohidrotic ectodermAl dysplAsiA (HED). In Addition to hAving impAired development of teeth, hAir, eccrine sweAt glAnds, And sAlivAry And mAmmAry glAnds, HED pAtients hAve eAr, nose And throAt diseAse. The mouse strAins TAbby (EdATA) And downless (EdArdl-J/dl-J) hAve rhinitis And otitis mediA due to loss of submucosAl glAnds in the upper AirwAy. We report thAt prenAtAl correction of EDAR signAlling in EdATA mice with the Agonist Anti-EDAR Antibody rescues the Auditory-tube submucosAl glAnds And prevents otitis mediA, rhinitis And nAsophAryngitis. The spArse- And wAvy-hAired (swh) rAt strAin cArries A mutAtion in the EdArAdd gene And hAs similAr cutAneous HED phenotypes to mouse models. We report thAt Auditory-tube submucosAl glAnds Are smAller in the homozygous mutAnt EdArAddswh/swh thAn those in unAffected heterozygous EdArAddswh/+ rAts, And thAt this predisposes them to otitis mediA. Furthermore, the pAthogenesis of otitis mediA in the rAt HED model differs from thAt in mice, As otitis mediA is the primAry pAthology, And rhinitis is A lAter-onset phenotype. These findings in rodent HED models imply thAt hypomorphic As well As null mutAtions in EDAR signAlling pAthwAy genes mAy predispose to otitis mediA in humAns. In Addition, this work suggests thAt the recent successful prenAtAl treAtment of X-linked HED (XLHED) in humAns mAy Also prevent eAr, nose And throAt diseAse, And provides diAgnostic criteriA thAt distinguish HED-AssociAted otitis mediA from chronic otitis mediA with effusion, which is common in children

  • MesenchymAl cell density And EDA signAlling interAct during skin pAtterning.
    2019
    Co-Authors: Lucy Freem, Debiao Zhao, Kevin J. Painter, Thomas E. Woolley, Eamonn A. Gaffney, Michael J. Mcgrew, Athanasia Tzika, Michel C. Milinkovitch, Pascal Schneider
    Abstract:

    (A) E6.5 skin cultured for 48 hours in 5 μM MTX, An inhibitor of cell proliferAtion. Primordium formAtion is detected by CTNNB1 expression. Inhibition of cell proliferAtion reduces the width of the pAtterned region, but the extent of the EDA expression wAve is unAffected. ScAle bAr: 2 mm. (B) SchemAtic of Assessment of the criticAl cell density At which pAtterning occurs. (C) And (D) MesenchymAl cell density within 100 μm of the edge of the pAtterned region of skin explAnts in the presence of (C) An ActivAtor (Fc-chEDA1) or (D) An inhibitor (Ecto-D2) of EDA/EDAR signAlling. Filled circles indicAte individuAl dAtA points; red bArs indicAte the meAn. StAtisticAl significAnce wAs cAlculAted using A Student t test (***p < 0.001). (E) E6.5 CAG-GFP skin explAnts cultured for 48 hours with 5 μM MTX, 10 μg/ml Ecto-D2, or both. ScAle bAr: 2 mm. (F) QuAntificAtion of pAtterned region widths, bAsed on FGF20 expression, shows reduction in pAtterned region of cotreAted sAmples compAred to eAch single treAtment. StAtisticAl significAnce wAs cAlculAted using A Student t test (***p < 0.001). (G) One-dimensionAl representAtion of A simulAtion of the network shown in Fig 1J, with peAks representing high cell density (condensAtes). Reduction of the wAve or of cell growth restricts the spreAd of pAttern, whereAs reduction of both hAs A stronger effect. The numericAl vAlues for C, D, F, And G cAn be found in S5 DAtA. E, embryonic dAy; EDA, EctodysplAsin A; EDAR, EDA receptor; GFP, green fluorescent protein; MTX, methotrexAte.

  • An EDA trAvelling wAve triggers feAther pAtterning.
    2019
    Co-Authors: Lucy Freem, Debiao Zhao, Kevin J. Painter, Thomas E. Woolley, Eamonn A. Gaffney, Michael J. Mcgrew, Athanasia Tzika, Michel C. Milinkovitch, Pascal Schneider
    Abstract:

    (A) E6.5 skin After 24 hours And 48 hours in culture showing expression of CTNNB1, EDAR, And EDA trAnscripts. ScAle bAr: 1 mm. (B) Whole-mount double in situ detection of CTNNB1 (orAnge) And EDA (purple) At E7.5. ScAle bAr: 200 μm. (C) qRT-PCR AnAlysis of FGF20 expression levels in E6.5 skin After 5 hours in 20 μM CHIR99021 (An ActivAtor of WNT/β-cAtenin signAlling), 50 ng/ml Fc-chEDA1 (An ActivAtor of EDAR signAlling), or A combinAtion of both. Filled circles indicAte individuAl dAtA points; red bArs indicAte the meAn. StAtisticAl significAnce wAs cAlculAted using A Student t test (*p < 0.05, **p < 0.01, ***p < 0.001). (D) CompArison of the periodicAlly pAtterned region, defined by FGF20 expression, in E6.5 skin cultured for 24 hours in the presence of either 15 μM LDN193189 (An inhibitor of BMP signAlling) or 2 μg/ml Fc-chEDA1. ScAle bAr: 1 mm. (E) QuAntificAtion of pAtterned region width in control, LDN193189-treAted, And Fc-chEDA1-treAted explAnts. StAtisticAl significAnce wAs cAlculAted using A Student t test (**p < 0.01, ***p < 0.001). (F) CompArison of pAtterned region width in E6.5 skin cultured for 48 hours in either control or 10 μg/ml Ecto-D2 (An inhibitor of EDA/EDAR signAlling) supplemented medium. ScAle bAr: 1 mm. (G) QuAntificAtion of pAtterned region width in control And Ecto-D2-treAted explAnts. StAtisticAl significAnce wAs cAlculAted using A Student t test (*p < 0.05). (H) Detection of FGF20 expression in in ovo control Antibody (Aprily2) And Ecto-D2-treAted embryos for compArison of feAther pAtterned region width. ScAle bAr: 2 mm. (I) QuAntificAtion of width of primordium cArrying dorsAl region in Ecto-D2 in ovo injected E8.5 embryos compAred to controls. StAtisticAl significAnce wAs cAlculAted using A Student t test (***p < 0.001). The numericAl vAlues for C, E, G, And I cAn be found in S3 DAtA. BMP, bone morphogenetic protein; E, embryonic dAy; EDA, EctodysplAsin A; EDAR, EDA receptor; qRT-PCR, quAntitAtive reverse trAnscription PCR.

  • EctodysplAsin A edA edA receptor signAlling And its phArmAcologicAl modulAtion
    Cytokine & Growth Factor Reviews, 2014
    Co-Authors: Christine Kowalczykquintas, Pascal Schneider
    Abstract:

    The TNF fAmily ligAnd EctodysplAsin A (EDA) regulAtes the induction, morphogenesis And/or mAintenAnce of skin-derived structures such As teeth, hAir, sweAt glAnds And severAl other glAnds. Deficiencies in the EDA - EDA receptor (EDAR) signAlling pAthwAy cAuse hypohidrotic ectodermAl dysplAsiA (HED). This syndrome is chArActerized by the Absence or mAlformAtion of severAl skin-derived AppendAges resulting in hypotrychosis, hypodontiA, heAt-intolerAnce, dry skin And dry eyes, susceptibility to AirwAys infections And crusting of vArious secretions. The EDA-EDAR system is An importAnt effector of cAnonicAl Wnt signAlling in developing skin AppendAges. It functions by stimulAting NF-κB-mediAted trAnscription of effectors or inhibitors of the Wnt, Sonic hedgehog (SHH), fibroblAst growth fActor (FGF) And trAnsforming growth fActor betA (TGFβ) pAthwAys thAt regulAte interActions within or between epitheliAl And mesenchymAl cells And tissues. In AnimAl models of EdA-deficiency, soluble EDAR Agonists cAn precisely correct clinicAlly relevAnt symptoms with low side effects even At high Agonist doses, indicAting thAt efficient negAtive feedbAck signAls occur in treAted tissues. HijAcking of the plAcentAl Antibody trAnsport system cAn help deliver Active molecules to developing foetuses in A timely mAnner. EDAR Agonists mAy serve to treAt certAin forms of ectodermAl dysplAsiA.

Irma Thesleff - One of the best experts on this subject based on the ideXlab platform.

  • EctodysplAsin hAs A duAl role in ectodermAl orgAnogenesis inhibition of bmp Activity And induction of shh expression
    Development, 2007
    Co-Authors: Marja Pummila, Irma Thesleff, Pascal Schneider, Johanna Laurikkala, Ingrid Fliniaux, Risto Jaatinen, Martyn J James, Marja L. Mikkola
    Abstract:

    EctodermAl orgAnogenesis is regulAted by inductive And reciprocAl signAlling cAscAdes thAt involve multiple signAl molecules in severAl conserved fAmilies. EctodysplAsin-A (EdA), A tumour necrosis fActor-like signAlling molecule, And its receptor EdAr Are required for the development of A number of ectodermAl orgAns in vertebrAtes. In mice, lAck of EdA leAds to fAilure in primAry hAir plAcode formAtion And missing or AbnormAlly shAped teeth, whereAs mice overexpressing EdA Are chArActerized by enlArged hAir plAcodes And supernumerAry teeth And mAmmAry glAnds. Here, we report two signAlling outcomes of the EdA pAthwAy: suppression of bone morphogenetic protein (Bmp) Activity And upregulAtion of sonic hedgehog (Shh) signAlling. RecombinAnt EdA counterActed Bmp4 Activity in developing teeth And, importAntly, inhibition of BMP Activity by exogenous noggin pArtiAlly restored primAry hAir plAcode formAtion in EdA -deficient skin in vitro, indicAting thAt suppression of Bmp Activity wAs compromised in the Absence of EdA. The downstreAm effects of the EdA pAthwAy Are likely to be mediAted by trAnscription fActor nucleAr fActor-κB (NF-κB), but the trAnscriptionAl tArgets of EdAr hAve remAined unknown. Using A quAntitAtive ApproAch, we show in cultured embryonic skin thAt EdA induced the expression of two Bmp inhibitors, Ccn2/Ctgf (CCN fAmily protein 2/connective tissue growth fActor) And follistAtin. Moreover, our dAtA indicAte thAt Shh is A likely trAnscriptionAl tArget of EdAr, but, unlike noggin, recombinAnt Shh wAs unAble to rescue primAry hAir plAcode formAtion in EdA -deficient skin explAnts.

  • mechAnisms of ectodermAl orgAnogenesis
    Developmental Biology, 2003
    Co-Authors: Johanna Pispa, Irma Thesleff
    Abstract:

    All ectodermAl orgAns, e.g. hAir, teeth, And mAny exocrine glAnds, originAte from two AdjAcent tissue lAyers: the epithelium And the mesenchyme. SimilAr sequentiAl And reciprocAl interActions between the epithelium And mesenchyme regulAte the eArly steps of development in All ectodermAl orgAns. GenerAlly, the mesenchyme provides the first instructive signAl, which is followed by the formAtion of the epitheliAl plAcode, An eArly signAling center. The plAcode buds into or out of the mesenchyme, And subsequent proliferAtion, cell movements, And differentiAtion of the epithelium And mesenchyme contribute to morphogenesis. The moleculAr signAls regulAting orgAnogenesis, such As molecules in the FGF, TGFβ, Wnt, And hedgehog fAmilies, regulAte the development of All ectodermAl AppendAges repeAtedly during AdvAncing morphogenesis And differentiAtion. In Addition, signAling by EctodysplAsin, A recently identified member of the TNF fAmily, And its receptor EdAr is required for ectodermAl orgAn development Across vertebrAte species. Here the current knowledge on the moleculAr regulAtion of the initiAtion, plAcode formAtion, And morphogenesis of ectodermAl orgAns is discussed with emphAsis on feAthers, hAir, And teeth.

  • regulAtion of hAir follicle development by the tnf signAl EctodysplAsin And its receptor edAr
    Development, 2002
    Co-Authors: Johanna Laurikkala, Johanna Pispa, Marja L. Mikkola, Pekka Nieminen, Hansung Jung, Xiuping Wang, Ulpu Saarialhokere, Juan Galceran, Rudi Grosschedl, Irma Thesleff
    Abstract:

    X-linked And AutosomAl forms of Anhidrotic ectodermAl dysplAsiA syndromes (HED) Are chArActerized by deficient development of severAl ectodermAl orgAns, including hAir, teeth And exocrine glAnds. The recent cloning of the genes thAt underlie these syndromes, EctodysplAsin (ED1) And the EctodysplAsin A receptor (EDAR), And their identificAtion As A novel TNF ligAnd-receptor pAir suggested A role for TNF signAling in embryonic morphogenesis. In the mouse, the genes of the spontAneous mutAtions TAbby (TA) And downless (dl) were identified As homologs of ED1 And EDAR, respectively. To gAin insight into the function of this signAling pAthwAy in development of skin And hAir follicles, we AnAlyzed the expression And regulAtion of EdA And EdAr in wild type As well As TAbby And Lef1 mutAnt mouse embryos. We show thAt EdA And EdAr expression is confined to the ectoderm And occurs in A pAttern thAt suggests A role of EctodysplAsin/EdAr signAling in the interActions between the ectodermAl compArtments And the formAtion And function of hAir plAcodes. By using skin explAnt cultures, we further show thAt this signAling pAthwAy is intimAtely AssociAted with interActions between the epitheliAl And mesenchymAl tissues. We Also find thAt TA mutAnts lAck completely the plAcodes of the first developing tylotrich hAirs, And thAt they do not show pAtterned expression of plAcodAl genes, including Bmp4, Lef1, Shh, Ptch And EdAr, And the genes for betA-cAtenin And Activin A. FinAlly, we identified Activin As A mesenchymAl signAl thAt stimulAtes EdAr expression And WNT As A signAl thAt induces EdA expression, suggesting A hierArchy of distinct signAling pAthwAys in the development of skin And hAir follicles. In conclusion, we suggest thAt EdA And EdAr Are AssociAted with the onset of ectodermAl pAtterning And thAt EctodysplAsin/edAr signAling Also regulAtes the morphogenesis of hAir follicles.

  • signAling And subcellulAr locAlizAtion of the tnf receptor edAr
    Experimental Cell Research, 2001
    Co-Authors: Petra Koppinen, Johanna Pispa, Irma Thesleff, Johanna Laurikkala, Marja L. Mikkola
    Abstract:

    TAbby And downless mutAnt mice hAve identicAl phenotypes chArActerized by deficient development of severAl ectodermAlly derived orgAns such As teeth, hAir, And sweAt glAnds. EdAr, encoded by the mouse downless gene And defective in humAn dominAnt And recessive forms of AutosomAl hypohidrotic ectodermAl dysplAsiA (EDA) syndrome, is A new member of the tumor necrosis fActor (TNF) receptor superfAmily. The ligAnd of EdAr is EctodysplAsin, A TNF-like molecule mutAted in the X-linked form of EDA And in the spontAneous mouse mutAnt TAbby. We hAve AnAlyzed the response of EdAr signAling in trAnsfected cells And show thAt it ActivAtes nucleAr fActor-kAppAB (NF-kAppAB) in A dose-dependent mAnner. When EdAr wAs expressed At low levels, the NF-kAppAB response wAs enhAnced by coexpression of EctodysplAsin. The ActivAtion of NF-kAppAB wAs greAtly reduced in cells expressing mutAnt forms of EdAr AssociAted with the downless phenotype. Overexpression of EdAr did not ActivAte SAPK/JNK nor p38 kinAse. Even though EdAr hArbors A deAth domAin its overexpression did not induce Apoptosis in Any of the four cell lines AnAlyzed, nor wAs there Any difference in Apoptosis in developing teeth of wild-type And TAbby mice. AdditionAlly, we show thAt the subcellulAr locAlizAtion of dominAnt negAtive Alleles of downless is drAmAticAlly different from thAt of recessive or wild-type Alleles. This together with differences in NF-kAppAB responses suggests An explAnAtion for the different mode of inheritAnce of the different downless Alleles.

  • EctodysplAsin A protein required for epitheliAl morphogenesis is A novel tnf homologue And promotes cell mAtrix Adhesion
    Mechanisms of Development, 1999
    Co-Authors: Marja L. Mikkola, Johanna Pispa, Maija Pekkanen, Juha Kere, Lars Paulin, Pekka Nieminen, Irma Thesleff
    Abstract:

    In the mouse TAbby (TA) mutAnt And humAn X-linked Anhidrotic ectodermAl dysplAsiA (EDA) syndrome development of severAl ectodermAl orgAns such As hAir, teeth, And sweAt glAnds is impAired. The gene behind TAbby And EDA hAs been cloned, And severAl AlternAtive trAnscripts hAve been isolAted. The protein product nAmed EctodysplAsin hAd no obvious function or prominent homology to other known gene products ApArt from A short collAgen-like sequence. We hAve isolAted two novel TA trAnscripts which Are vAriAnts of the longest isoform of TAbby, nAmed TA-A. In situ hybridizAtions reveAled TA-A to be the mAjor trAnscript in the developing embryo. It wAs detected in the endoderm of eArly embryos And subsequently in specific locAtions in the neuroepithelium And ectoderm. Unexpectedly, sequence AnAlysis of the most C-terminAl domAin of TA reveAled thAt EctodysplAsin is A novel member of the tumor necrosis fActor (TNF) ligAnd superfAmily. Mouse EctodysplAsin wAs biochemicAlly And functionAlly chArActerized, And shown to be A glycosylAted, oligomeric type II membrAne protein (N-terminus inside), All chArActeristics typicAl to TNF-like proteins. Members of the TNF fAmily Are criticAlly involved in host defence And immune response often mediAting either Apoptosis or cell survivAl. Expression of TA in severAl epitheliAl cell lines did not result in prominent chAnges in cell morphology And did not promote Apoptosis. InsteAd, it wAs shown to promote cell Adhesion to extrAcellulAr mAtrix, A function consistent with its postulAted role in epitheliAl-mesenchymAl interActions regulAting the development of ectodermAl AppendAges. EctodysplAsin is the first TNF-like signAling molecule described known to be required for epitheliAl morphogenesis.

Marja L. Mikkola - One of the best experts on this subject based on the ideXlab platform.

  • replAying evolutionAry trAnsitions from the dentAl fossil record
    Nature, 2014
    Co-Authors: Enni Harjunmaa, Marja L. Mikkola, Kerstin Seidel, Teemu J Hakkinen, Elodie Renvoise, Ian J Corfe, Aki Kallonen, Zhaoqun Zhang, Alistair R Evans, Isaac Salazarciudad
    Abstract:

    The evolutionAry relAtionships of extinct species Are AscertAined primArily through the AnAlysis of morphologicAl chArActers. ChArActer inter-dependencies cAn hAve A substAntiAl effect on evolutionAry interpretAtions, but the developmentAl underpinnings of chArActer inter-dependence remAin obscure becAuse experiments frequently do not provide detAiled resolution of morphologicAl chArActers. Here we show experimentAlly And computAtionAlly how grAduAl modificAtion of development differentiAlly Affects chArActers in the mouse dentition. We found thAt intermediAte phenotypes could be produced by grAduAlly Adding EctodysplAsin A (EDA) protein in culture to tooth explAnts cArrying A null mutAtion in the tooth-pAtterning gene EdA. By identifying development-bAsed chArActer inter-dependencies, we show how to predict morphologicAl pAtterns of teeth Among mAmmAliAn species. FinAlly, in vivo inhibition of sonic hedgehog signAlling in EdA null teeth enAbled us to reproduce chArActers deep in the rodent Ancestry. TAken together, evolutionArily informAtive trAnsitions cAn be experimentAlly reproduced, thereby providing development-bAsed expectAtions for chArActer-stAte trAnsitions used in evolutionAry studies.

  • biologicAl Activity of EctodysplAsin A is conditioned by its collAgen And hepArAn sulfAte proteoglycAn binding domAins
    Journal of Biological Chemistry, 2009
    Co-Authors: Lee Kim Swee, Marja L. Mikkola, Aubry Tardivel, Laure Willen, Manuel Favre, Stéphane Demotz, Olivier Gaide, Karine Ingoldsalamin, Pascal Schneider
    Abstract:

    MutAtions in the TNF fAmily ligAnd EDA1 cAuse X-linked hypohidrotic ectodermAl dysplAsiA (XLHED), A condition chArActerized by defective development of skin AppendAges. The EDA1 protein displAys A proteolytic processing site responsible for its conversion to A soluble form, A collAgen domAin, And A trimeric TNF homology domAin (THD) thAt binds the receptor EDAR. In-frAme deletions in the collAgen domAin reduced the thermAl stAbility of EDA1. RemovAl of the collAgen domAin decreAsed its Activity About 100-fold, As meAsured with nAturAl And engineered EDA1-responsive cell lines. The collAgen domAin could be functionAlly replAced by multimerizAtion domAins or by cross-linking Antibodies, suggesting thAt it functions As An oligomerizAtion unit. Surprisingly, mAture soluble EDA1 contAining the collAgen domAin wAs poorly Active when Administered in newborn, EDA-deficient (TAbby) mice. This wAs due to A short stretch of bAsic Amino Acids locAted At the N terminus of the collAgen domAin thAt confers EDA1 with proteoglycAn binding Ability. In contrAst to wild-type EDA1, EDA1 with mutAtions in this bAsic sequence wAs A potent inducer of tAil hAir development in vivo. Thus, the collAgen domAin ActivAtes EDA1 by multimerizAtion, whereAs the proteoglycAn-binding domAin mAy restrict the distribution of endogeneous EDA1 in vivo.

  • EctodysplAsin hAs A duAl role in ectodermAl orgAnogenesis inhibition of bmp Activity And induction of shh expression
    Development, 2007
    Co-Authors: Marja Pummila, Irma Thesleff, Pascal Schneider, Johanna Laurikkala, Ingrid Fliniaux, Risto Jaatinen, Martyn J James, Marja L. Mikkola
    Abstract:

    EctodermAl orgAnogenesis is regulAted by inductive And reciprocAl signAlling cAscAdes thAt involve multiple signAl molecules in severAl conserved fAmilies. EctodysplAsin-A (EdA), A tumour necrosis fActor-like signAlling molecule, And its receptor EdAr Are required for the development of A number of ectodermAl orgAns in vertebrAtes. In mice, lAck of EdA leAds to fAilure in primAry hAir plAcode formAtion And missing or AbnormAlly shAped teeth, whereAs mice overexpressing EdA Are chArActerized by enlArged hAir plAcodes And supernumerAry teeth And mAmmAry glAnds. Here, we report two signAlling outcomes of the EdA pAthwAy: suppression of bone morphogenetic protein (Bmp) Activity And upregulAtion of sonic hedgehog (Shh) signAlling. RecombinAnt EdA counterActed Bmp4 Activity in developing teeth And, importAntly, inhibition of BMP Activity by exogenous noggin pArtiAlly restored primAry hAir plAcode formAtion in EdA -deficient skin in vitro, indicAting thAt suppression of Bmp Activity wAs compromised in the Absence of EdA. The downstreAm effects of the EdA pAthwAy Are likely to be mediAted by trAnscription fActor nucleAr fActor-κB (NF-κB), but the trAnscriptionAl tArgets of EdAr hAve remAined unknown. Using A quAntitAtive ApproAch, we show in cultured embryonic skin thAt EdA induced the expression of two Bmp inhibitors, Ccn2/Ctgf (CCN fAmily protein 2/connective tissue growth fActor) And follistAtin. Moreover, our dAtA indicAte thAt Shh is A likely trAnscriptionAl tArget of EdAr, but, unlike noggin, recombinAnt Shh wAs unAble to rescue primAry hAir plAcode formAtion in EdA -deficient skin explAnts.

  • regulAtion of hAir follicle development by the tnf signAl EctodysplAsin And its receptor edAr
    Development, 2002
    Co-Authors: Johanna Laurikkala, Johanna Pispa, Marja L. Mikkola, Pekka Nieminen, Hansung Jung, Xiuping Wang, Ulpu Saarialhokere, Juan Galceran, Rudi Grosschedl, Irma Thesleff
    Abstract:

    X-linked And AutosomAl forms of Anhidrotic ectodermAl dysplAsiA syndromes (HED) Are chArActerized by deficient development of severAl ectodermAl orgAns, including hAir, teeth And exocrine glAnds. The recent cloning of the genes thAt underlie these syndromes, EctodysplAsin (ED1) And the EctodysplAsin A receptor (EDAR), And their identificAtion As A novel TNF ligAnd-receptor pAir suggested A role for TNF signAling in embryonic morphogenesis. In the mouse, the genes of the spontAneous mutAtions TAbby (TA) And downless (dl) were identified As homologs of ED1 And EDAR, respectively. To gAin insight into the function of this signAling pAthwAy in development of skin And hAir follicles, we AnAlyzed the expression And regulAtion of EdA And EdAr in wild type As well As TAbby And Lef1 mutAnt mouse embryos. We show thAt EdA And EdAr expression is confined to the ectoderm And occurs in A pAttern thAt suggests A role of EctodysplAsin/EdAr signAling in the interActions between the ectodermAl compArtments And the formAtion And function of hAir plAcodes. By using skin explAnt cultures, we further show thAt this signAling pAthwAy is intimAtely AssociAted with interActions between the epitheliAl And mesenchymAl tissues. We Also find thAt TA mutAnts lAck completely the plAcodes of the first developing tylotrich hAirs, And thAt they do not show pAtterned expression of plAcodAl genes, including Bmp4, Lef1, Shh, Ptch And EdAr, And the genes for betA-cAtenin And Activin A. FinAlly, we identified Activin As A mesenchymAl signAl thAt stimulAtes EdAr expression And WNT As A signAl thAt induces EdA expression, suggesting A hierArchy of distinct signAling pAthwAys in the development of skin And hAir follicles. In conclusion, we suggest thAt EdA And EdAr Are AssociAted with the onset of ectodermAl pAtterning And thAt EctodysplAsin/edAr signAling Also regulAtes the morphogenesis of hAir follicles.

  • signAling And subcellulAr locAlizAtion of the tnf receptor edAr
    Experimental Cell Research, 2001
    Co-Authors: Petra Koppinen, Johanna Pispa, Irma Thesleff, Johanna Laurikkala, Marja L. Mikkola
    Abstract:

    TAbby And downless mutAnt mice hAve identicAl phenotypes chArActerized by deficient development of severAl ectodermAlly derived orgAns such As teeth, hAir, And sweAt glAnds. EdAr, encoded by the mouse downless gene And defective in humAn dominAnt And recessive forms of AutosomAl hypohidrotic ectodermAl dysplAsiA (EDA) syndrome, is A new member of the tumor necrosis fActor (TNF) receptor superfAmily. The ligAnd of EdAr is EctodysplAsin, A TNF-like molecule mutAted in the X-linked form of EDA And in the spontAneous mouse mutAnt TAbby. We hAve AnAlyzed the response of EdAr signAling in trAnsfected cells And show thAt it ActivAtes nucleAr fActor-kAppAB (NF-kAppAB) in A dose-dependent mAnner. When EdAr wAs expressed At low levels, the NF-kAppAB response wAs enhAnced by coexpression of EctodysplAsin. The ActivAtion of NF-kAppAB wAs greAtly reduced in cells expressing mutAnt forms of EdAr AssociAted with the downless phenotype. Overexpression of EdAr did not ActivAte SAPK/JNK nor p38 kinAse. Even though EdAr hArbors A deAth domAin its overexpression did not induce Apoptosis in Any of the four cell lines AnAlyzed, nor wAs there Any difference in Apoptosis in developing teeth of wild-type And TAbby mice. AdditionAlly, we show thAt the subcellulAr locAlizAtion of dominAnt negAtive Alleles of downless is drAmAticAlly different from thAt of recessive or wild-type Alleles. This together with differences in NF-kAppAB responses suggests An explAnAtion for the different mode of inheritAnce of the different downless Alleles.

Aubry Tardivel - One of the best experts on this subject based on the ideXlab platform.

  • The JournAl of ExperimentAl Medicine CORRESPONDENCE
    2013
    Co-Authors: Karine Ingold, Aubry Tardivel, Adrian Zumsteg, Quynh-giao Steiner, Teresa G. Cachero, Fang Qiang, Leonid Gorelik, Susan L. Kalled, Hans Acha-orbea, Paul D. Rennert
    Abstract:

    BAFF, B cell ActivAting fActor of the TNF fAmily; BAFF-R, BAFF receptor; BCMA, B cell mAturAtion Antigen; COMP, cArtilAge mAtrix oligomeric protein; EDA, EctodysplAsin A; TACI, trAnsmembrAne ActivAtor And cAlcium signAl–modulAting cyclophilin ligAnd interActor. B cell ActivAting fActor of the tumor necrosis fActor (TNF) fAmily (BAFF) And A proliferAtioninducing ligAnd (APRIL) Are closely relAted ligAnds within the TNF superfAmily thAt plAy importAnt roles in B lymphocyte biology. Both ligAnds shAre two receptors—trAnsmembrAne ActivAtor And cAlcium signAl–modulAting cyclophilin ligAnd interActor (TACI) And B cell mAturAtion Antigen (BCMA)—thAt Are predominAntly expressed on B cells. In Addition, BAFF specificAlly binds BAFF receptor, whereAs the nAture of A postulAted APRIL-specific recepto

  • moleculAr And therApeutic chArActerizAtion of Anti EctodysplAsin A receptor edAr Agonist monoclonAl Antibodies
    Journal of Biological Chemistry, 2011
    Co-Authors: Christine Kowalczyk, Aubry Tardivel, Laure Willen, Margret L. Casal, Elizabeth A. Mauldin, Olivier Gaide, Nathalie Dunkel, Giovanna Badic, Annelise Etter, Manuel Favre
    Abstract:

    The TNF fAmily ligAnd EctodysplAsin A (EDA) And its receptor EDAR Are required for proper development of skin AppendAges such As hAir, teeth, And eccrine sweAt glAnds. Loss of function mutAtions in the EdA gene cAuse X-linked hypohidrotic ectodermAl dysplAsiA (XLHED), A condition thAt cAn be AmeliorAted in mice And dogs by timely AdministrAtion of recombinAnt EDA. In this study, severAl Agonist Anti-EDAR monoclonAl Antibodies were generAted thAt cross-reAct with the extrAcellulAr domAins of humAn, dog, rAt, mouse, And chicken EDAR. Their hAlf-life in Adult mice wAs About 11 dAys. They induced tAil hAir And sweAt glAnd formAtion when Administered to newborn EDA-deficient TAbby mice, with An EC50 of 0.1 to 0.7 mg/kg. DivAlency wAs necessAry And sufficient for this therApeutic Activity. Only some Antibodies were Also Agonists in An in vitro surrogAte Activity AssAy bAsed on the ActivAtion of the Apoptotic FAs pAthwAy. Activity in this AssAy correlAted with smAll dissociAtion constAnts. When Administered in utero in mice or At birth in dogs, Agonist Antibodies reverted severAl ectodermAl dysplAsiA feAtures, including tooth morphology. These Antibodies Are therefore predicted to efficiently trigger EDAR signAling in mAny vertebrAte species And will be pArticulArly suited for long term treAtments.

  • FunctionAl AnAlysis of EctodysplAsin-A mutAtions cAusing selective tooth Agenesis
    European Journal of Human Genetics, 2010
    Co-Authors: Gabriele Mues, Aubry Tardivel, Laure Willen, Hitesh Kapadia, Robyn Seaman, Sylvia Frazier-bowers, Pascal Schneider, Rena N. D'souza
    Abstract:

    MutAtions of the EctodysplAsin-A ( EDA ) gene Are generAlly AssociAted with the syndrome hypohidrotic ectodermAl dysplAsiA (MIM 305100), but they cAn Also mAnifest As selective, non-syndromic tooth Agenesis (MIM300606). We hAve performed An in vitro functionAl AnAlysis of six selective tooth Agenesis-cAusing EDA mutAtions (one novel And five known) thAt Are locAted in the C-terminAl tumor necrosis fActor homology domAin of the protein. Our study reveAls thAt expression, receptor binding or signAling cApAbility of the mutAnt EDA1 proteins is only impAired in contrAst to syndrome-cAusing mutAtions, which we hAve previously shown to Abolish EDA1 expression, receptor binding or signAling. Our results support A model in which the development of the humAn dentition, especiAlly of Anterior teeth, requires the highest level of EDA-receptor signAling, whereAs other ectodermAl AppendAges, including posterior teeth, hAve less stringent requirements And form normAlly in response to EDA mutAtions with reduced Activity.

  • biologicAl Activity of EctodysplAsin A is conditioned by its collAgen And hepArAn sulfAte proteoglycAn binding domAins
    Journal of Biological Chemistry, 2009
    Co-Authors: Lee Kim Swee, Marja L. Mikkola, Aubry Tardivel, Laure Willen, Manuel Favre, Stéphane Demotz, Olivier Gaide, Karine Ingoldsalamin, Pascal Schneider
    Abstract:

    MutAtions in the TNF fAmily ligAnd EDA1 cAuse X-linked hypohidrotic ectodermAl dysplAsiA (XLHED), A condition chArActerized by defective development of skin AppendAges. The EDA1 protein displAys A proteolytic processing site responsible for its conversion to A soluble form, A collAgen domAin, And A trimeric TNF homology domAin (THD) thAt binds the receptor EDAR. In-frAme deletions in the collAgen domAin reduced the thermAl stAbility of EDA1. RemovAl of the collAgen domAin decreAsed its Activity About 100-fold, As meAsured with nAturAl And engineered EDA1-responsive cell lines. The collAgen domAin could be functionAlly replAced by multimerizAtion domAins or by cross-linking Antibodies, suggesting thAt it functions As An oligomerizAtion unit. Surprisingly, mAture soluble EDA1 contAining the collAgen domAin wAs poorly Active when Administered in newborn, EDA-deficient (TAbby) mice. This wAs due to A short stretch of bAsic Amino Acids locAted At the N terminus of the collAgen domAin thAt confers EDA1 with proteoglycAn binding Ability. In contrAst to wild-type EDA1, EDA1 with mutAtions in this bAsic sequence wAs A potent inducer of tAil hAir development in vivo. Thus, the collAgen domAin ActivAtes EDA1 by multimerizAtion, whereAs the proteoglycAn-binding domAin mAy restrict the distribution of endogeneous EDA1 in vivo.

  • SignificAnt correction of diseAse After postnAtAl AdministrAtion of recombinAnt EctodysplAsin A in cAnine X-linked ectodermAl dysplAsiA.
    The American Journal of Human Genetics, 2007
    Co-Authors: Margret L. Casal, Aubry Tardivel, John R. Lewis, Elizabeth A. Mauldin, Karine Ingold, Manuel Favre, Fabrice Paradies, Stéphane Demotz, Olivier Gaide, Pascal Schneider
    Abstract:

    PAtients with defective EctodysplAsin A (EDA) Are Affected by X-linked hypohidrotic ectodermAl dysplAsiA (XLHED), A condition chArActerized by spArse hAir, inAbility to sweAt, decreAsed lAcrimAtion, frequent pulmonAry infections, And missing And mAlformed teeth. The cAnine model of XLHED wAs used to study the developmentAl impAct of EDA on secondAry dentition, since dogs hAve An entirely brAchyodont, diphyodont dentition similAr to thAt in humAns, As opposed to mice, which hAve only permAnent teeth (monophyodont dentition), some of which Are very different (ArAdiculAr hypsodont) thAn brAchyodont humAn teeth. Also, clinicAl signs in humAns And dogs with XLHED Are virtuAlly identicAl, whereAs severAl Are missing in the murine equivAlent. In our model, the geneticAlly missing EDA wAs compensAted for by postnAtAl intrAvenous AdministrAtion of soluble recombinAnt EDA. UntreAted XLHED dogs hAve An incomplete set of conicAlly shAped teeth similAr to those seen in humAn pAtients with XLHED. After treAtment with EDA, significAnt normAlizAtion of Adult teeth wAs Achieved in four of five XLHED dogs. Moreover, treAtment restored normAl lAcrimAtion And resistAnce to eye And AirwAy infections And improved sweAting Ability. These results not only provide proof of concept for A potentiAl treAtment of this orphAn diseAse but Also demonstrAte An essentiAl role of EDA in the development of secondAry dentition.

Johanna Pispa - One of the best experts on this subject based on the ideXlab platform.

  • mechAnisms of ectodermAl orgAnogenesis
    Developmental Biology, 2003
    Co-Authors: Johanna Pispa, Irma Thesleff
    Abstract:

    All ectodermAl orgAns, e.g. hAir, teeth, And mAny exocrine glAnds, originAte from two AdjAcent tissue lAyers: the epithelium And the mesenchyme. SimilAr sequentiAl And reciprocAl interActions between the epithelium And mesenchyme regulAte the eArly steps of development in All ectodermAl orgAns. GenerAlly, the mesenchyme provides the first instructive signAl, which is followed by the formAtion of the epitheliAl plAcode, An eArly signAling center. The plAcode buds into or out of the mesenchyme, And subsequent proliferAtion, cell movements, And differentiAtion of the epithelium And mesenchyme contribute to morphogenesis. The moleculAr signAls regulAting orgAnogenesis, such As molecules in the FGF, TGFβ, Wnt, And hedgehog fAmilies, regulAte the development of All ectodermAl AppendAges repeAtedly during AdvAncing morphogenesis And differentiAtion. In Addition, signAling by EctodysplAsin, A recently identified member of the TNF fAmily, And its receptor EdAr is required for ectodermAl orgAn development Across vertebrAte species. Here the current knowledge on the moleculAr regulAtion of the initiAtion, plAcode formAtion, And morphogenesis of ectodermAl orgAns is discussed with emphAsis on feAthers, hAir, And teeth.

  • regulAtion of hAir follicle development by the tnf signAl EctodysplAsin And its receptor edAr
    Development, 2002
    Co-Authors: Johanna Laurikkala, Johanna Pispa, Marja L. Mikkola, Pekka Nieminen, Hansung Jung, Xiuping Wang, Ulpu Saarialhokere, Juan Galceran, Rudi Grosschedl, Irma Thesleff
    Abstract:

    X-linked And AutosomAl forms of Anhidrotic ectodermAl dysplAsiA syndromes (HED) Are chArActerized by deficient development of severAl ectodermAl orgAns, including hAir, teeth And exocrine glAnds. The recent cloning of the genes thAt underlie these syndromes, EctodysplAsin (ED1) And the EctodysplAsin A receptor (EDAR), And their identificAtion As A novel TNF ligAnd-receptor pAir suggested A role for TNF signAling in embryonic morphogenesis. In the mouse, the genes of the spontAneous mutAtions TAbby (TA) And downless (dl) were identified As homologs of ED1 And EDAR, respectively. To gAin insight into the function of this signAling pAthwAy in development of skin And hAir follicles, we AnAlyzed the expression And regulAtion of EdA And EdAr in wild type As well As TAbby And Lef1 mutAnt mouse embryos. We show thAt EdA And EdAr expression is confined to the ectoderm And occurs in A pAttern thAt suggests A role of EctodysplAsin/EdAr signAling in the interActions between the ectodermAl compArtments And the formAtion And function of hAir plAcodes. By using skin explAnt cultures, we further show thAt this signAling pAthwAy is intimAtely AssociAted with interActions between the epitheliAl And mesenchymAl tissues. We Also find thAt TA mutAnts lAck completely the plAcodes of the first developing tylotrich hAirs, And thAt they do not show pAtterned expression of plAcodAl genes, including Bmp4, Lef1, Shh, Ptch And EdAr, And the genes for betA-cAtenin And Activin A. FinAlly, we identified Activin As A mesenchymAl signAl thAt stimulAtes EdAr expression And WNT As A signAl thAt induces EdA expression, suggesting A hierArchy of distinct signAling pAthwAys in the development of skin And hAir follicles. In conclusion, we suggest thAt EdA And EdAr Are AssociAted with the onset of ectodermAl pAtterning And thAt EctodysplAsin/edAr signAling Also regulAtes the morphogenesis of hAir follicles.

  • signAling And subcellulAr locAlizAtion of the tnf receptor edAr
    Experimental Cell Research, 2001
    Co-Authors: Petra Koppinen, Johanna Pispa, Irma Thesleff, Johanna Laurikkala, Marja L. Mikkola
    Abstract:

    TAbby And downless mutAnt mice hAve identicAl phenotypes chArActerized by deficient development of severAl ectodermAlly derived orgAns such As teeth, hAir, And sweAt glAnds. EdAr, encoded by the mouse downless gene And defective in humAn dominAnt And recessive forms of AutosomAl hypohidrotic ectodermAl dysplAsiA (EDA) syndrome, is A new member of the tumor necrosis fActor (TNF) receptor superfAmily. The ligAnd of EdAr is EctodysplAsin, A TNF-like molecule mutAted in the X-linked form of EDA And in the spontAneous mouse mutAnt TAbby. We hAve AnAlyzed the response of EdAr signAling in trAnsfected cells And show thAt it ActivAtes nucleAr fActor-kAppAB (NF-kAppAB) in A dose-dependent mAnner. When EdAr wAs expressed At low levels, the NF-kAppAB response wAs enhAnced by coexpression of EctodysplAsin. The ActivAtion of NF-kAppAB wAs greAtly reduced in cells expressing mutAnt forms of EdAr AssociAted with the downless phenotype. Overexpression of EdAr did not ActivAte SAPK/JNK nor p38 kinAse. Even though EdAr hArbors A deAth domAin its overexpression did not induce Apoptosis in Any of the four cell lines AnAlyzed, nor wAs there Any difference in Apoptosis in developing teeth of wild-type And TAbby mice. AdditionAlly, we show thAt the subcellulAr locAlizAtion of dominAnt negAtive Alleles of downless is drAmAticAlly different from thAt of recessive or wild-type Alleles. This together with differences in NF-kAppAB responses suggests An explAnAtion for the different mode of inheritAnce of the different downless Alleles.

  • EctodysplAsin A protein required for epitheliAl morphogenesis is A novel tnf homologue And promotes cell mAtrix Adhesion
    Mechanisms of Development, 1999
    Co-Authors: Marja L. Mikkola, Johanna Pispa, Maija Pekkanen, Juha Kere, Lars Paulin, Pekka Nieminen, Irma Thesleff
    Abstract:

    In the mouse TAbby (TA) mutAnt And humAn X-linked Anhidrotic ectodermAl dysplAsiA (EDA) syndrome development of severAl ectodermAl orgAns such As hAir, teeth, And sweAt glAnds is impAired. The gene behind TAbby And EDA hAs been cloned, And severAl AlternAtive trAnscripts hAve been isolAted. The protein product nAmed EctodysplAsin hAd no obvious function or prominent homology to other known gene products ApArt from A short collAgen-like sequence. We hAve isolAted two novel TA trAnscripts which Are vAriAnts of the longest isoform of TAbby, nAmed TA-A. In situ hybridizAtions reveAled TA-A to be the mAjor trAnscript in the developing embryo. It wAs detected in the endoderm of eArly embryos And subsequently in specific locAtions in the neuroepithelium And ectoderm. Unexpectedly, sequence AnAlysis of the most C-terminAl domAin of TA reveAled thAt EctodysplAsin is A novel member of the tumor necrosis fActor (TNF) ligAnd superfAmily. Mouse EctodysplAsin wAs biochemicAlly And functionAlly chArActerized, And shown to be A glycosylAted, oligomeric type II membrAne protein (N-terminus inside), All chArActeristics typicAl to TNF-like proteins. Members of the TNF fAmily Are criticAlly involved in host defence And immune response often mediAting either Apoptosis or cell survivAl. Expression of TA in severAl epitheliAl cell lines did not result in prominent chAnges in cell morphology And did not promote Apoptosis. InsteAd, it wAs shown to promote cell Adhesion to extrAcellulAr mAtrix, A function consistent with its postulAted role in epitheliAl-mesenchymAl interActions regulAting the development of ectodermAl AppendAges. EctodysplAsin is the first TNF-like signAling molecule described known to be required for epitheliAl morphogenesis.

  • The Anhidrotic EctodermAl DysplAsiA Gene (EDA) Undergoes AlternAtive Splicing And Encodes EctodysplAsin-A with Deletion MutAtions in CollAgenous RepeAts
    Human Molecular Genetics, 1998
    Co-Authors: Mònica Bayés, Johanna Pispa, Irma Thesleff, Anand K. Srivastava, Andrew J. Hartung, Sini Ezer, Juha Kere
    Abstract:

    Anhidrotic ectodermAl dysplAsiA (EDA) is An X-linked recessive disorder which Affects ectodermAl structures. A cDNA encoding A 135 Amino Acid protein with mutAtions in 5-10% of EDA pAtients hAs been reported. We hAve built up A complete splicing mAp of the EDA gene And chArActerized the longest And whAt most probAbly represents the full-length EDA trAnscript, EDA-A. It encodes A 391 Amino Acid trAnsmembrAne protein with A short collAgenous domAin, (Gly-X-Y) 19 , And is highly homologous to the protein mutAted in TAbby mice (TA-A). Four new trAnscripts thAt code for truncAted proteins lAcking the collAgenous domAin were Also detected. The splice vAriAnts show different expression pAtterns in eight tissues AnAlyzed, suggesting A regulAtory mechAnism for gene expression. The EDA-A form of the protein is trAnsported to the cell membrAne And induces rounding of the cells, properties Also AssociAted with the 135 Amino Acid isoform. We hAve determined the genomic orgAnizAtion And the exon-intron boundAries of the EDA gene. SSCP AnAlysis of the nine exons corresponding to EDA-A Allowed the identificAtion of mutAtions in 12 out of 15 EDA pAtients. Interestingly, three mutAtions removed either two or four of the Gly-X-Y repeAts without interrupting the reAding frAme, thus suggesting A functionAl role for the collAgenous domAin. Our results will Allow mutAtion diAgnostics in the mAjority of pAtients.

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