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Irma Thesleff - One of the best experts on this subject based on the ideXlab platform.
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identification of dkk4 as a target of eda a1 EDAR pathway reveals an unexpected role of ectodysplasin as inhibitor of wnt signalling in ectodermal placodes
Developmental Biology, 2008Co-Authors: Ingrid Fliniaux, Marja L Mikkola, Sylvie Lefebvre, Irma ThesleffAbstract:Abstract The development of epithelial appendages, including hairs, glands and teeth starts from ectodermal placodes, and is regulated by interplay of stimulatory and inhibitory signals. Ectodysplasin-A1 (Eda-A1) and Wnts are high in hierarchy of placode activators. To identify direct targets of ectodysplasin pathway, we performed microarray profiling of genes differentially regulated by short exposure to recombinant Eda-A1 in embryonic eda−/− skin explants. Surprisingly, there were only two genes with obvious involvement in Wnt pathway: dkk4 (most highly induced gene in the screen), and lrp4. Both genes colocalized with Eda-A1 receptor EDAR in placodes of ectodermal organs. They were upregulated upon EDAR activation while several other Wnt associated genes previously suggested as EDAR targets were unaffected. However, low dkk4 and lrp4 expression was retained in the absence of NF-κB signalling in eda−/− hair placodes. We provide evidence that this expression was dependent on Wnt activity present prior to Eda-A1/EDAR signalling. Dkk4 was recently suggested as a key Wnt antagonist regulating lateral inhibition essential for correct patterning of hair follicles. Several pieces of evidence suggest Lrp4 as a Wnt inhibitor, as well. The finding that Eda-A1 induces placode inhibitors was unexpected, and underlines the importance of delicate fine-tuning of signalling during placode formation.
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tooth patterning and enamel formation can be manipulated by misexpression of tnf receptor EDAR
Developmental Dynamics, 2004Co-Authors: Johanna Pispa, Marja L Mikkola, Petra Koppinen, Tuija Mustonen, Aapo T Kangas, Pirjoliisa Lukinmaa, Jukka Jernvall, Irma ThesleffAbstract:Signaling by EDAR, a tumor necrosis factor receptor, is required for the development of ectodermal organs. Mutations in EDAR or other molecules of the same signaling pathway cause ectodermal dysplasias in humans and mice. In these diseases, teeth are missing or malformed, and the development of hairs and several glands is hypoplastic. During tooth and hair development, EDAR expression becomes patterned to ectodermal placodes and signaling centers. This localization has been suggested to be required for organogenesis. We have expressed EDAR throughout the ectoderm using the keratin 14 promoter and show that this misexpression disrupts tooth patterning and differentiation. Tooth shape and cusp number are differentially affected, depending on the amount of transgene expression. In addition, tooth enamel formation is defective in a dose-dependent manner. We speculate that the tooth patterning defects are caused by ectopic EDAR activity outside the signaling centers.
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regulation of hair follicle development by the tnf signal ectodysplasin and its receptor EDAR
Development, 2002Co-Authors: Johanna Laurikkala, Johanna Pispa, Marja L Mikkola, Pekka Nieminen, Hansung Jung, Xiuping Wang, Ulpu Saarialhokere, Juan Galceran, Rudi Grosschedl, Irma ThesleffAbstract: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.
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signaling and subcellular localization of the tnf receptor EDAR
Experimental Cell Research, 2001Co-Authors: Petra Koppinen, Johanna Pispa, Irma Thesleff, Johanna Laurikkala, Marja L MikkolaAbstract: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.
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tnf signaling via the ligand receptor pair ectodysplasin and EDAR controls the function of epithelial signaling centers and is regulated by wnt and activin during tooth organogenesis
Developmental Biology, 2001Co-Authors: Johanna Laurikkala, Johanna Pispa, Marja L Mikkola, Pekka Nieminen, Petra Koppinen, Juan Galceran, Rudi Grosschedl, Tuija Mustonen, Thomas Aberg, Irma ThesleffAbstract:Abstract Ectodermal dysplasia syndromes affect the development of several organs, including hair, teeth, and glands. The recent cloning of two genes responsible for these syndromes has led to the identification of a novel TNF family ligand, ectodysplasin, and TNF receptor, EDAR. This has indicated a developmental regulatory role for TNFs for the first time. Our in situ hybridization analysis of the expression of ectodysplasin (encoded by the Tabby gene) and EDAR (encoded by the downless gene) during mouse tooth morphogenesis showed that they are expressed in complementary patterns exclusively in ectodermal tissue layer. EDAR was expressed reiteratively in signaling centers regulating key steps in morphogenesis. The analysis of the effects of eight signaling molecules in the TGFβ, FGF, Hh, Wnt, and EGF families in tooth explant cultures revealed that the expression of EDAR was induced by activinβA, whereas Wnt6 induced ectodysplasin expression. Moreover, ectodysplasin expression was downregulated in branchial arch epithelium and in tooth germs of Lef1 mutant mice, suggesting that signaling by ectodysplasin is regulated by LEF-1-mediated Wnt signals. The analysis of the signaling centers in tooth germs of Tabby mice (ectodysplasin null mutants) indicated that in the absence of ectodysplasin the signaling centers were small. However, no downstream targets of ectodysplasin signaling were identified among several genes expressed in the signaling centers. We conclude that ectodysplasin functions as a planar signal between ectodermal compartments and regulates the function, but not the induction, of epithelial signaling centers. This TNF signaling is tightly associated with epithelial–mesenchymal interactions and with other signaling pathways regulating organogenesis. We suggest that activin signaling from mesenchyme induces the expression of the TNF receptor EDAR in the epithelial signaling centers, thus making them responsive to Wnt-induced ectodysplasin from the nearby ectoderm. This is the first demonstration of integration of the Wnt, activin, and TNF signaling pathways.
Marja L Mikkola - One of the best experts on this subject based on the ideXlab platform.
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anti EDAR agonist antibody therapy resolves palate defects in pax9 mice
Journal of Dental Research, 2017Co-Authors: Shihai Jia, Pascal Schneider, Marja L Mikkola, Jing Zhou, Yinshen Wee, Rena N DsouzaAbstract:To date, surgical interventions are the only means by which craniofacial anomalies can be corrected so that function, esthetics, and the sense of well-being are restored in affected individuals. Unfortunately, for patients with cleft palate-one of the most common of congenital birth defects-treatment following surgery is prolonged over a lifetime and often involves multidisciplinary regimens. Hence, there is a need to understand the molecular pathways that control palatogenesis and to translate such information for the development of noninvasive therapies that can either prevent or correct cleft palates in humans. Here, we use the well-characterized model of the Pax9-/- mouse, which displays a consistent phenotype of a secondary cleft palate, to test a novel therapeutic. Specifically, we demonstrate that the controlled intravenous delivery of a novel mouse monoclonal antibody replacement therapy, which acts as an agonist for the ectodysplasin (Eda) pathway, can resolve cleft palate defects in Pax9-/- embryos in utero. Such pharmacological interventions did not reverse the arrest in tooth, thymus, and parathyroid gland development, suggesting that the relationship of Pax9 to the Eda/EDAR pathway is both unique and essential for palatogenesis. Expression analyses and unbiased gene expression profiling studies offer a molecular explanation for the resolution of palatal defects, showing that Eda and EDAR-related genes are expressed in normal palatal tissues and that the Eda/EDAR signaling pathway is downstream of Pax9 in palatogenesis. Taken together, our data uncover a unique relationship between Pax9 and the Eda/EDAR signaling pathway that can be further exploited for the development of noninvasive, safe, and effective therapies for the treatment of cleft palate conditions and other single-gene disorders affecting the craniofacial complex.
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Anti-EDAR Agonist Antibody Therapy Resolves Palate Defects in Pax9-/- Mice:
Journal of Dental Research, 2017Co-Authors: Shihai Jia, Pascal Schneider, Marja L Mikkola, Jing Zhou, Yinshen Wee, Rena N. D'souzaAbstract:To date, surgical interventions are the only means by which craniofacial anomalies can be corrected so that function, esthetics, and the sense of well-being are restored in affected individuals. Unfortunately, for patients with cleft palate-one of the most common of congenital birth defects-treatment following surgery is prolonged over a lifetime and often involves multidisciplinary regimens. Hence, there is a need to understand the molecular pathways that control palatogenesis and to translate such information for the development of noninvasive therapies that can either prevent or correct cleft palates in humans. Here, we use the well-characterized model of the Pax9-/- mouse, which displays a consistent phenotype of a secondary cleft palate, to test a novel therapeutic. Specifically, we demonstrate that the controlled intravenous delivery of a novel mouse monoclonal antibody replacement therapy, which acts as an agonist for the ectodysplasin (Eda) pathway, can resolve cleft palate defects in Pax9-/- embryos in utero. Such pharmacological interventions did not reverse the arrest in tooth, thymus, and parathyroid gland development, suggesting that the relationship of Pax9 to the Eda/EDAR pathway is both unique and essential for palatogenesis. Expression analyses and unbiased gene expression profiling studies offer a molecular explanation for the resolution of palatal defects, showing that Eda and EDAR-related genes are expressed in normal palatal tissues and that the Eda/EDAR signaling pathway is downstream of Pax9 in palatogenesis. Taken together, our data uncover a unique relationship between Pax9 and the Eda/EDAR signaling pathway that can be further exploited for the development of noninvasive, safe, and effective therapies for the treatment of cleft palate conditions and other single-gene disorders affecting the craniofacial complex.
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the EDAR subfamily in hair and exocrine gland development
Advances in Experimental Medicine and Biology, 2011Co-Authors: Marja L MikkolaAbstract:The EDAR subfamily of TNFRs includes three receptors, EDAR, Troy, and XEDAR, with similar extracellular but unrelated intracellular domains. All three receptors are expressed in the embryonic ectoderm and/or its appendages, such as hair follicle, tooth, and sweat and mammary gland. While the function of the EDAR pathway, mutated in human hypohidrotic ectodermal syndrome (HED), has been conserved during vertebrate evolution, considerably less is known about the physiological role of Troy and XEDAR. Research on the EDAR pathway has focused on hair follicle and tooth biology, but recent progress has been made in uncovering its relevance in morphogenesis of glandular appendages as well.
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biological activity of ectodysplasin a is conditioned by its collagen and heparan sulfate proteoglycan binding domains
Journal of Biological Chemistry, 2009Co-Authors: Lee Kim Swee, Aubry Tardivel, Laure Willen, Manuel Favre, Stéphane Demotz, Olivier Gaide, Marja L Mikkola, Karine Ingoldsalamin, Pascal SchneiderAbstract: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.
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identification of dkk4 as a target of eda a1 EDAR pathway reveals an unexpected role of ectodysplasin as inhibitor of wnt signalling in ectodermal placodes
Developmental Biology, 2008Co-Authors: Ingrid Fliniaux, Marja L Mikkola, Sylvie Lefebvre, Irma ThesleffAbstract:Abstract The development of epithelial appendages, including hairs, glands and teeth starts from ectodermal placodes, and is regulated by interplay of stimulatory and inhibitory signals. Ectodysplasin-A1 (Eda-A1) and Wnts are high in hierarchy of placode activators. To identify direct targets of ectodysplasin pathway, we performed microarray profiling of genes differentially regulated by short exposure to recombinant Eda-A1 in embryonic eda−/− skin explants. Surprisingly, there were only two genes with obvious involvement in Wnt pathway: dkk4 (most highly induced gene in the screen), and lrp4. Both genes colocalized with Eda-A1 receptor EDAR in placodes of ectodermal organs. They were upregulated upon EDAR activation while several other Wnt associated genes previously suggested as EDAR targets were unaffected. However, low dkk4 and lrp4 expression was retained in the absence of NF-κB signalling in eda−/− hair placodes. We provide evidence that this expression was dependent on Wnt activity present prior to Eda-A1/EDAR signalling. Dkk4 was recently suggested as a key Wnt antagonist regulating lateral inhibition essential for correct patterning of hair follicles. Several pieces of evidence suggest Lrp4 as a Wnt inhibitor, as well. The finding that Eda-A1 induces placode inhibitors was unexpected, and underlines the importance of delicate fine-tuning of signalling during placode formation.
Johanna Pispa - One of the best experts on this subject based on the ideXlab platform.
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tooth patterning and enamel formation can be manipulated by misexpression of tnf receptor EDAR
Developmental Dynamics, 2004Co-Authors: Johanna Pispa, Marja L Mikkola, Petra Koppinen, Tuija Mustonen, Aapo T Kangas, Pirjoliisa Lukinmaa, Jukka Jernvall, Irma ThesleffAbstract:Signaling by EDAR, a tumor necrosis factor receptor, is required for the development of ectodermal organs. Mutations in EDAR or other molecules of the same signaling pathway cause ectodermal dysplasias in humans and mice. In these diseases, teeth are missing or malformed, and the development of hairs and several glands is hypoplastic. During tooth and hair development, EDAR expression becomes patterned to ectodermal placodes and signaling centers. This localization has been suggested to be required for organogenesis. We have expressed EDAR throughout the ectoderm using the keratin 14 promoter and show that this misexpression disrupts tooth patterning and differentiation. Tooth shape and cusp number are differentially affected, depending on the amount of transgene expression. In addition, tooth enamel formation is defective in a dose-dependent manner. We speculate that the tooth patterning defects are caused by ectopic EDAR activity outside the signaling centers.
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regulation of hair follicle development by the tnf signal ectodysplasin and its receptor EDAR
Development, 2002Co-Authors: Johanna Laurikkala, Johanna Pispa, Marja L Mikkola, Pekka Nieminen, Hansung Jung, Xiuping Wang, Ulpu Saarialhokere, Juan Galceran, Rudi Grosschedl, Irma ThesleffAbstract: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.
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signaling and subcellular localization of the tnf receptor EDAR
Experimental Cell Research, 2001Co-Authors: Petra Koppinen, Johanna Pispa, Irma Thesleff, Johanna Laurikkala, Marja L MikkolaAbstract: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.
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tnf signaling via the ligand receptor pair ectodysplasin and EDAR controls the function of epithelial signaling centers and is regulated by wnt and activin during tooth organogenesis
Developmental Biology, 2001Co-Authors: Johanna Laurikkala, Johanna Pispa, Marja L Mikkola, Pekka Nieminen, Petra Koppinen, Juan Galceran, Rudi Grosschedl, Tuija Mustonen, Thomas Aberg, Irma ThesleffAbstract:Abstract Ectodermal dysplasia syndromes affect the development of several organs, including hair, teeth, and glands. The recent cloning of two genes responsible for these syndromes has led to the identification of a novel TNF family ligand, ectodysplasin, and TNF receptor, EDAR. This has indicated a developmental regulatory role for TNFs for the first time. Our in situ hybridization analysis of the expression of ectodysplasin (encoded by the Tabby gene) and EDAR (encoded by the downless gene) during mouse tooth morphogenesis showed that they are expressed in complementary patterns exclusively in ectodermal tissue layer. EDAR was expressed reiteratively in signaling centers regulating key steps in morphogenesis. The analysis of the effects of eight signaling molecules in the TGFβ, FGF, Hh, Wnt, and EGF families in tooth explant cultures revealed that the expression of EDAR was induced by activinβA, whereas Wnt6 induced ectodysplasin expression. Moreover, ectodysplasin expression was downregulated in branchial arch epithelium and in tooth germs of Lef1 mutant mice, suggesting that signaling by ectodysplasin is regulated by LEF-1-mediated Wnt signals. The analysis of the signaling centers in tooth germs of Tabby mice (ectodysplasin null mutants) indicated that in the absence of ectodysplasin the signaling centers were small. However, no downstream targets of ectodysplasin signaling were identified among several genes expressed in the signaling centers. We conclude that ectodysplasin functions as a planar signal between ectodermal compartments and regulates the function, but not the induction, of epithelial signaling centers. This TNF signaling is tightly associated with epithelial–mesenchymal interactions and with other signaling pathways regulating organogenesis. We suggest that activin signaling from mesenchyme induces the expression of the TNF receptor EDAR in the epithelial signaling centers, thus making them responsive to Wnt-induced ectodysplasin from the nearby ectoderm. This is the first demonstration of integration of the Wnt, activin, and TNF signaling pathways.
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tnf signaling via the ligand receptor pair ectodysplasin and EDAR controls the function of epithelial signaling centers and is regulated by wnt and activin during tooth organogenesis
Developmental Biology, 2001Co-Authors: Johanna Laurikkala, Johanna Pispa, Marja L Mikkola, Pekka Nieminen, Petra Koppinen, Juan Galceran, Rudi Grosschedl, Tuija Mustonen, Thomas Aberg, Irma ThesleffAbstract:Abstract Ectodermal dysplasia syndromes affect the development of several organs, including hair, teeth, and glands. The recent cloning of two genes responsible for these syndromes has led to the identification of a novel TNF family ligand, ectodysplasin, and TNF receptor, EDAR. This has indicated a developmental regulatory role for TNFs for the first time. Our in situ hybridization analysis of the expression of ectodysplasin (encoded by the Tabby gene) and EDAR (encoded by the downless gene) during mouse tooth morphogenesis showed that they are expressed in complementary patterns exclusively in ectodermal tissue layer. EDAR was expressed reiteratively in signaling centers regulating key steps in morphogenesis. The analysis of the effects of eight signaling molecules in the TGFβ, FGF, Hh, Wnt, and EGF families in tooth explant cultures revealed that the expression of EDAR was induced by activinβA, whereas Wnt6 induced ectodysplasin expression. Moreover, ectodysplasin expression was downregulated in branchial arch epithelium and in tooth germs of Lef1 mutant mice, suggesting that signaling by ectodysplasin is regulated by LEF-1-mediated Wnt signals. The analysis of the signaling centers in tooth germs of Tabby mice (ectodysplasin null mutants) indicated that in the absence of ectodysplasin the signaling centers were small. However, no downstream targets of ectodysplasin signaling were identified among several genes expressed in the signaling centers. We conclude that ectodysplasin functions as a planar signal between ectodermal compartments and regulates the function, but not the induction, of epithelial signaling centers. This TNF signaling is tightly associated with epithelial–mesenchymal interactions and with other signaling pathways regulating organogenesis. We suggest that activin signaling from mesenchyme induces the expression of the TNF receptor EDAR in the epithelial signaling centers, thus making them responsive to Wnt-induced ectodysplasin from the nearby ectoderm. This is the first demonstration of integration of the Wnt, activin, and TNF signaling pathways.
Johanna Laurikkala - One of the best experts on this subject based on the ideXlab platform.
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regulation of hair follicle development by the tnf signal ectodysplasin and its receptor EDAR
Development, 2002Co-Authors: Johanna Laurikkala, Johanna Pispa, Marja L Mikkola, Pekka Nieminen, Hansung Jung, Xiuping Wang, Ulpu Saarialhokere, Juan Galceran, Rudi Grosschedl, Irma ThesleffAbstract: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.
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signaling and subcellular localization of the tnf receptor EDAR
Experimental Cell Research, 2001Co-Authors: Petra Koppinen, Johanna Pispa, Irma Thesleff, Johanna Laurikkala, Marja L MikkolaAbstract: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.
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tnf signaling via the ligand receptor pair ectodysplasin and EDAR controls the function of epithelial signaling centers and is regulated by wnt and activin during tooth organogenesis
Developmental Biology, 2001Co-Authors: Johanna Laurikkala, Johanna Pispa, Marja L Mikkola, Pekka Nieminen, Petra Koppinen, Juan Galceran, Rudi Grosschedl, Tuija Mustonen, Thomas Aberg, Irma ThesleffAbstract:Abstract Ectodermal dysplasia syndromes affect the development of several organs, including hair, teeth, and glands. The recent cloning of two genes responsible for these syndromes has led to the identification of a novel TNF family ligand, ectodysplasin, and TNF receptor, EDAR. This has indicated a developmental regulatory role for TNFs for the first time. Our in situ hybridization analysis of the expression of ectodysplasin (encoded by the Tabby gene) and EDAR (encoded by the downless gene) during mouse tooth morphogenesis showed that they are expressed in complementary patterns exclusively in ectodermal tissue layer. EDAR was expressed reiteratively in signaling centers regulating key steps in morphogenesis. The analysis of the effects of eight signaling molecules in the TGFβ, FGF, Hh, Wnt, and EGF families in tooth explant cultures revealed that the expression of EDAR was induced by activinβA, whereas Wnt6 induced ectodysplasin expression. Moreover, ectodysplasin expression was downregulated in branchial arch epithelium and in tooth germs of Lef1 mutant mice, suggesting that signaling by ectodysplasin is regulated by LEF-1-mediated Wnt signals. The analysis of the signaling centers in tooth germs of Tabby mice (ectodysplasin null mutants) indicated that in the absence of ectodysplasin the signaling centers were small. However, no downstream targets of ectodysplasin signaling were identified among several genes expressed in the signaling centers. We conclude that ectodysplasin functions as a planar signal between ectodermal compartments and regulates the function, but not the induction, of epithelial signaling centers. This TNF signaling is tightly associated with epithelial–mesenchymal interactions and with other signaling pathways regulating organogenesis. We suggest that activin signaling from mesenchyme induces the expression of the TNF receptor EDAR in the epithelial signaling centers, thus making them responsive to Wnt-induced ectodysplasin from the nearby ectoderm. This is the first demonstration of integration of the Wnt, activin, and TNF signaling pathways.
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tnf signaling via the ligand receptor pair ectodysplasin and EDAR controls the function of epithelial signaling centers and is regulated by wnt and activin during tooth organogenesis
Developmental Biology, 2001Co-Authors: Johanna Laurikkala, Johanna Pispa, Marja L Mikkola, Pekka Nieminen, Petra Koppinen, Juan Galceran, Rudi Grosschedl, Tuija Mustonen, Thomas Aberg, Irma ThesleffAbstract:Abstract Ectodermal dysplasia syndromes affect the development of several organs, including hair, teeth, and glands. The recent cloning of two genes responsible for these syndromes has led to the identification of a novel TNF family ligand, ectodysplasin, and TNF receptor, EDAR. This has indicated a developmental regulatory role for TNFs for the first time. Our in situ hybridization analysis of the expression of ectodysplasin (encoded by the Tabby gene) and EDAR (encoded by the downless gene) during mouse tooth morphogenesis showed that they are expressed in complementary patterns exclusively in ectodermal tissue layer. EDAR was expressed reiteratively in signaling centers regulating key steps in morphogenesis. The analysis of the effects of eight signaling molecules in the TGFβ, FGF, Hh, Wnt, and EGF families in tooth explant cultures revealed that the expression of EDAR was induced by activinβA, whereas Wnt6 induced ectodysplasin expression. Moreover, ectodysplasin expression was downregulated in branchial arch epithelium and in tooth germs of Lef1 mutant mice, suggesting that signaling by ectodysplasin is regulated by LEF-1-mediated Wnt signals. The analysis of the signaling centers in tooth germs of Tabby mice (ectodysplasin null mutants) indicated that in the absence of ectodysplasin the signaling centers were small. However, no downstream targets of ectodysplasin signaling were identified among several genes expressed in the signaling centers. We conclude that ectodysplasin functions as a planar signal between ectodermal compartments and regulates the function, but not the induction, of epithelial signaling centers. This TNF signaling is tightly associated with epithelial–mesenchymal interactions and with other signaling pathways regulating organogenesis. We suggest that activin signaling from mesenchyme induces the expression of the TNF receptor EDAR in the epithelial signaling centers, thus making them responsive to Wnt-induced ectodysplasin from the nearby ectoderm. This is the first demonstration of integration of the Wnt, activin, and TNF signaling pathways.
Marcin Szmit - One of the best experts on this subject based on the ideXlab platform.
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the oldest homo erectus buried lithic horizon from the eastern saharan africa EDAR 7 an acheulean assemblage with kombewa method from the eastern desert sudan
PLOS ONE, 2021Co-Authors: Miroslaw Masojc, Ju Yong Kim, Joanna Krupakurzynowska, Young Kwan Sohn, Maciej Ehlert, Grzegorz Michalec, Marzena Cendrowska, Eric Andrieux, Simon J Armitage, Marcin SzmitAbstract:Although essential for reconstructing hominin behaviour during the Early Palaeolithic, only a handful of Acheulean sites have been dated in the Eastern Sahara region. This is due to the scarcity of sites for this time period and the lack of datable material. However, recent excavations in the Atbara region (Sudan) have provided unique opportunities to analyse and date Acheulean stone tools. We report here on EDAR 7, part of a cluster of Acheulean and Middle Stone Age (MSA) sites that were recently discovered in the Eastern Desert Atbara River (EDAR) region, located in the Eastern Desert (Sudan) far from the Nile valley. At EDAR 7, a 3.5 metre sedimentary sequence was excavated, allowing an Acheulean assemblage to be investigated using a combination of sedimentology, stone tool studies and optically stimulated luminescence dating (OSL). The site has delivered a complete Acheulean knapping chaine operatoire, providing new information about the Saharan Acheulean. The EDAR 7 site is interpreted as a remnant of a campsite based on the co-occurrence of two reduction modes: one geared towards the production of Large Cutting Tools (LCTs), and the other based on the flaking of small debitage and production of flake tools. Particularly notable in the EDAR 7 assemblage is the abundance of cleavers, most of which display evidence of flake production. Implementation of giant Kombewa flakes was also observed. A geometric morphometric analysis of hand-axes was conducted to verify a possible Late Acheulean assemblage standardisation in the Nubian Sahara. In addition, the analysis of micro-traces and wear on the artefacts has provided information on the use history of the Acheulean stone tools. Sediment analyses and OSL dating show that the EDAR 7 sequence contains the oldest Acheulean encampment remains in the Eastern Sahara, dated to the MIS 11 or earlier. This confirms that Homo erectus occupied the EDAR region during Middle Pleistocene humid periods, and demonstrates that habitable corridors existed between the Ethiopian Highlands, the Nile and the Red Sea coast, allowing population dispersals across the continent and out of it.
