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At least 19 recordsLinked to original sources

PubMed2002

Regulation of hair follicle development by the TNF signal ectodysplasin and its receptor Edar.

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.

Activins↗

PubMed2001

Signaling and subcellular localization of the TNF receptor Edar.

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.

Alleles↗

PubMed2002

TRAF6-deficient mice display hypohidrotic ectodermal dysplasia.

Tumor necrosis factor receptor (TNFR)-associated factor 6 (TRAF6) is an adapter protein that links signals from members of the TNFR superfamily and Toll/IL-1 receptor family to activation of transcription factors NFkappaB and AP-1. Analysis of TRAF6-deficient mice revealed that TRAF6 is essential for normal bone formation and establishment of immune and inflammatory systems. Here we report that TRAF6 deficiency results in defective development of epidermal appendixes, including guard hair follicles, sweat glands, sebaceous glands of back skin, and modified sebaceous glands such as meibomian glands, anal glands, and preputial glands. Except the sebaceous gland impairment, these abnormal phenotypes are identical to those observed in Tabby (Ta), downless (dl), and crinkled (cr) mice, which are models of hypohidrotic (anhidrotic) ectodermal dysplasia in human. beta-catenin and mucosal addressin cell adhesion molecule-1, an early marker of developing guard-hair follicles is absent in the skin of TRAF6-deficient embryos. Thus, TRAF6 is essential for development of epidermal appendixes. TRAF6 does not associate with the cytoplasmic tail of the dl protein (DL)/ectodysplasin receptor (EDAR) receptor, which, when mutated, results in hypohidrotic (anhidrotic) ectodermal dysplasia. However, TRAF6 associates with X-linked ectodysplasin-A2 receptor (XEDAR) and TNFR super family expressed on the mouse embryo (TROY/toxicity and JNK inducer (TAJ), which are EDAR-related members of the TNFR superfamily that are expressed at high level in epidermal appendixes. Furthermore, TRAF6 is essential for the XEDAR-mediated NFkappaB activation. Our results suggest that TRAF6 may transduce signals emanating from XEDAR or TROY/TAJ that are associated with development of epidermal appendixes.

Animals↗

PubMed2001

The medaka rs-3 locus required for scale development encodes ectodysplasin-A receptor.

The bodies of most teleost fish species are covered with specialized subepithelial structures known as scales. The scale is an epithelial appendage that differentiates from the dermal mesenchyme. Mammals, on the other hand, have no scales, but instead their bodies are covered with hair. Although their appearances are quite different, scales and hair can be considered structurally similar in that both of them are epithelial appendages distributed over the body surface in an orderly pattern. This analogy suggests that they may have the same evolutionary origin. But, to date, no molecular evidence has been presented that links scales and hair. A mutation at the rs-3 locus of medaka (Oryzias latipes) leads to almost complete loss of scales. We demonstrated that the rs-3 locus encodes ectodysplasin-A receptor (EDAR), which is required for the initiation of hair development in mammals. We identified a novel transposon inserted in the first intron of EDAR, which causes aberrant splicing. This work shows that EDAR is required for scale development in fish and suggests that it is an evolutionarily conserved molecule that is required for the development of epithelial appendages in vertebrates.

Amino Acid Sequence↗

PubMedDate not supplied

Ectodysplasin signaling in development.

Ectodysplasin (Eda), a signaling molecule belonging to the tumor necrosis factor family, is required for normal development of several ectodermally derived organs in humans and mice. Two closely related isoforms of ectodysplasin, Eda-A1 and Eda-A2, have been described which bind to and activate two different receptors, Edar and X-linked Eda-A2 receptor (Xedar), respectively. Mutations in Eda, Edar or other molecules of this signaling pathway cause ectodermal dysplasias characterized by defective development of teeth, hairs, and several exocrine glands such as sweat glands presumably due to impaired NF-kappaB response. Studies with mice either lacking the functional proteins of Edar pathway or overexpressing the ligand or receptor suggest that Eda-A1-Edar signaling has multiple roles in ectodermal organ development regulating their initiation, morphogenesis, and differentiation.

Animals↗

PubMed2003

Stimulation of ectodermal organ development by Ectodysplasin-A1.

Organs developing as ectodermal appendages share similar early morphogenesis and molecular mechanisms. Ectodysplasin, a signaling molecule belonging to the tumor necrosis factor family, and its receptor Edar are required for normal development of several ectodermal organs in humans and mice. We have overexpressed two splice forms of ectodysplasin, Eda-A1 and Eda-A2, binding to Edar and another TNF receptor, Xedar, respectively, under the keratin 14 (K14) promoter in the ectoderm of transgenic mice. Eda-A2 overexpression did not cause a detectable phenotype. On the contrary, overexpression of Eda-A1 resulted in alterations in a variety of ectodermal organs, most notably in extra organs. Hair development was initiated continuously from E14 until birth, and in addition, the transgenic mice had supernumerary teeth and mammary glands, phenotypes not reported previously in transgenic mice. Also, hair composition and structure was abnormal, and the cycling of hairs was altered so that the growth phase (anagen) was prolonged. Both hairs and nails grew longer than normal. Molar teeth were of abnormal shape, and enamel formation was severely disturbed in incisors. Furthermore, sweat gland function was stimulated and sebaceous glands were enlarged. We conclude that ectodysplasin-Edar signaling has several roles in ectodermal organ development controlling their initiation, as well as morphogenesis and differentiation.

Animals↗

PubMed2002

Recent advances in understanding of the molecular basis of anhidrotic ectodermal dysplasia: discovery of a ligand, ectodysplasin A and its two receptors.

Recent developments of the investigations on the molecular basis of anhidrotic ectodermal dysplasia are reviewed. Identification of the major product of the EDA gene (ectodysplasin A), a protein belonging to a group of TNF ligands, and molecular cloning of the cDNA, encoding its receptor (EDAR), a member of the TNF receptor family, are presented. The role of an alternative EDA receptor, localised on the X chromosome (XEDAR) in the developmental control of the differentiation of skin appendages, is discussed. Recent findings have elucidated the cause of the autosomal forms of EDA, both dominant and recessive, and indicated an important role of a signal transduction pathway involving a protein product of the NEMO gene and the transcription factor NFkappaB in the differentiation of skin appendages.

Cloning, Molecular↗

PubMed2003

Ectodysplasin, Edar and TNFRSF19 are expressed in complementary and overlapping patterns during mouse embryogenesis.

Ectodysplasin (Eda), a member of the tumor necrosis factor (TNF) superfamily, and its receptor Edar are necessary components of ectodermal organ development. Analysis of their expression patterns and mutant phenotypes has shown that during mouse hair and tooth development they may be involved in signalling between separate epithelial compartments. Here we have analysed ectodysplasin and Edar expression in other embryonic mouse tissues, and show that Edar mRNA is confined to the epithelium. Ectodysplasin and Edar are expressed in separate epithelial compartments in the developing brain and the lacrimal gland. In the salivary gland ectodysplasin is expressed in the mesenchyme and Edar in the epithelium. This is the first indication of ectodysplasin-Edar signalling between the epithelium and the mesenchyme. We also studied the expression pattern of a related TNF receptor, TNFRSF19, and show that it is expressed in an overlapping domain with Edar in the tooth, mammary gland, whiskers, and limb bud suggesting a potentially redundant role.

Amino Acid Sequence↗

PubMed2000

The ectodermal dysplasia receptor activates the nuclear factor-kappaB, JNK, and cell death pathways and binds to ectodysplasin A.

The ectodermal dysplasia receptor (EDAR) is a recently isolated member of the tumor necrosis factor receptor family that has been shown to play a key role in the process of ectodermal differentiation. We present evidence that EDAR is capable of activating the nuclear factor-kappaB, JNK, and caspase-independent cell death pathways and that these activities are impaired in mutants lacking its death domain or those associated with anhidrotic ectodermal dysplasia and the downless phenotype. Although EDAR possesses a death domain, it did not interact with the death domain-containing adaptor proteins TRADD and FADD. EDAR successfully interacted with various TRAF family members; however, a dominant-negative mutant of TRAF2 was incapable of blocking EDAR-induced nuclear factor-kappaB or JNK activation. Collectively, the above results suggest that EDAR utilizes a novel signal transduction pathway. Finally, ectodysplasin A can physically interact with the extracellular domain of EDAR and thus represents its biological ligand.

Cell Death↗

PubMed2000

Two-amino acid molecular switch in an epithelial morphogen that regulates binding to two distinct receptors.

Ectodysplasin, a member of the tumor necrosis factor family, is encoded by the anhidrotic ectodermal dysplasia (EDA) gene. Mutations in EDA give rise to a clinical syndrome characterized by loss of hair, sweat glands, and teeth. EDA-A1 and EDA-A2 are two isoforms of ectodysplasin that differ only by an insertion of two amino acids. This insertion functions to determine receptor binding specificity, such that EDA-A1 binds only the receptor EDAR, whereas EDA-A2 binds only the related, but distinct, X-linked ectodysplasin-A2 receptor (XEDAR). In situ binding and organ culture studies indicate that EDA-A1 and EDA-A2 are differentially expressed and play a role in epidermal morphogenesis.

Amino Acid Sequence↗

PubMed2001

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.

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 TGFbeta, FGF, Hh, Wnt, and EGF families in tooth explant cultures revealed that the expression of edar was induced by activinbetaA, 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.

Activins↗

PubMed2002

Death receptor signaling giving life to ectodermal organs.

A new tumor necrosis factor (TNF) pathway has been identified that has an important function in the regulation of embryonic development. Three key components of this pathway are previously unknown proteins: the TNF ligand ectodysplasin (also known as EDA), its death domain-containing receptor EDAR, and the death domain adapter molecule EDARADD. This pathway was discovered and delineated through the cloning of genes that cause human hypohidrotic ectodermal dysplasia (HED) syndromes and by analysis of the corresponding mouse mutants (Tabby, downless, and crinkled) showing defects in hair, teeth, and several exocrine glands. EDAR signaling is mediated by the activation of nuclear factor kappa B, but other downstream targets are not known. Ectodysplasin-EDAR signaling mediates cell interactions within the ectoderm and regulates the initiation and morphogenesis of hair and teeth. It is also necessary for the development of fish scales, indicating that this pathway and its function have been conserved during the evolution of ectodermal organs.

Animals↗

PubMed2003

Permanent correction of an inherited ectodermal dysplasia with recombinant EDA.

X-linked hypohidrotic ectodermal dysplasia (XLHED; OMIM 305100) is a genetic disorder characterized by absence or deficient function of hair, teeth and sweat glands. Affected children may experience life-threatening high fever resulting from reduced ability to sweat. Mice with the Tabby phenotype share many symptoms with human XLHED patients because both phenotypes are caused by mutations of the syntenic ectodysplasin A gene (Eda) on the X chromosome. Two main splice variants of Eda, encoding EDA1 and EDA2, engage the tumor necrosis factor (TNF) family receptors EDAR and XEDAR, respectively. The EDA1 protein, acting through EDAR, is essential for proper formation of skin appendages; the functions of EDA2 and XEDAR are not known. EDA1 must be proteolytically processed to a soluble form to be active. Here, we show that treatment of pregnant Tabby mice with a recombinant form of EDA1, engineered to cross the placental barrier, permanently rescues the Tabby phenotype in the offspring. Notably, sweat glands can also be induced by EDA1 after birth. This is the first example of a developmental genetic defect that can be permanently corrected by short-term treatment with a recombinant protein.

Amino Acid Sequence↗

PubMed2001

Ectodysplasin-A1 is sufficient to rescue both hair growth and sweat glands in Tabby mice.

Mutations in the human ectodysplasin-A (EDA) are responsible for the most common form of the ectodermal dysplasia and the defective orthologous gene in mice produces the tabby phenotype, suggesting its vital role in the development of hair, sweat glands and teeth. Among several EDA splice isoforms, the most common and the longest EDA splice isoforms, EDA-A1 and EDA-A2, differing by only two amino acids, activate NF-kappaB-promoted transcription by binding to distinct receptors, EDAR and XEDAR. The extent to which any particular isoform is sufficient for the formation of hair, sweat glands or teeth has remained unclear. Here we report that transgenic expression of the mouse EDA-A1 isoform in tabby (EDA-less) males rescued development of several skin appendages. The transgenic tabby mice showed almost complete restoration of hair growth, dermal ridges, sweat glands and molars. The number of hair follicles in the transgenic mice is the same as in wild-type; though the development of follicles and associated glands varies from indistinguishable from wild-type to smaller and/or only partially formed. These results suggest that the other EDA isoforms may not be absolutely required for skin appendage formation, but consistent with distinctive temporal and spatial expression of the EDA-A2 isoform, are likely required for appropriate timing and completeness of development. Our data provide the first direct physiological evidence that EDA-A1 is a key regulator of hair follicle and sweat gland initiation; its soluble ligand form could aid in deriving therapeutic reagents for conditions affecting hair and sweat gland formation.

Animals↗

PubMed2002

The NF-kappaB signalling pathway in human diseases: from incontinentia pigmenti to ectodermal dysplasias and immune-deficiency syndromes.

The transcription factor NF-kappaB regulates the expression of numerous genes controlling the immune and stress responses, inflammatory reaction, cell adhesion, and protection against apoptosis. Incontinentia pigmenti (IP) is the first genetic disorder to be ascribed to NF-kappaB dysfunction. IP is an X-linked dominant genodermatosis antenatally lethal in males. A complex rearrangement of the NEMO (NF-kappaB essential modulator) gene accounts for 85% of IP patients, and results in undetectable NEMO protein and absent NF-kappaB activation. On the other hand, hypohidrotic/anhidrotic ectodermal dysplasia (HED/EDA) has been ascribed to at least three genes also involved in NF-kappaB activation: ectodysplasin (EDA1), EDA-receptor (EDAR) and EDAR-associated death domain (EDARADD). During hair follicle morphogenesis, EDAR is activated by ectodysplasin, and uses EDARADD as an adapter to build a signal transducing complex that leads to NF-kappaB activation. Hence, several forms of HED/EDA also result from impaired activation of the NF-kappaB cascade. Finally, hypomorphic NEMO mutations have been found to cause anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID), whilst stop codon mutations cause a more severe phenotype associating EDA-ID with osteopetrosis and lymphoedema (OL-EDA-ID). The immunological and infectious features observed in patients result from impaired NF-kappaB signalling, including cellular response to LPS, IL-1beta, IL-18, TNF-alpha, Tlr2 and CD40 ligand. Consistently, mouse knockout models have shown the essential role of NF-kappaB in the immune, inflammatory and apoptotic responses. Unravelling the molecular bases of other forms of EDA not associated with mutations in NEMO will possibly implicate other components of the NF-kappaB signalling pathway.

Animals↗

PubMed2002

Identification of a novel death domain-containing adaptor molecule for ectodysplasin-A receptor that is mutated in crinkled mice.

Hypohydrotic Ectodermal Dysplasia (HED) is a genetic disease seen in humans and mice. It is characterized by loss of hair, sweat glands, and teeth. The predominant X-linked form results from mutations in ectodysplasin-A (EDA), a TNF-like ligand. A phenotypically indistinguishable autosomal form of the disease results from mutations in the receptor for EDA (EDAR). EDAR is a NF-kappaB-activating, death domain-containing member of the TNF receptor family. crinkled, a distinct autosomal form of HED, was discovered in a mouse strain in which both the ligand (EDA) and receptor (EDAR) were wild-type, suggestive of a disruption further downstream in the signaling pathway. Employing a forward genetic approach, we have cloned crinkled (CR) and find it to encode a novel death domain-containing adaptor. crinkled binds EDAR through a homotypic death domain interaction and mediates engagement of the NF-kappaB pathway, possibly by recruiting TRAF2 to the receptor-signaling complex. This is an unprecedented example of naturally occurring mutations in ligand, receptor, or adaptor giving rise to the same phenotypic disease characterized by a defect in the proper development of epidermal appendages.

Adaptor Proteins, Signal Transducing↗

PubMed2000

TROY, a newly identified member of the tumor necrosis factor receptor superfamily, exhibits a homology with Edar and is expressed in embryonic skin and hair follicles.

In a signal sequence trap screening of the murine brain, we identified a new member of the tumor necrosis factor receptor superfamily designated TROY. TROY is a type I membrane protein of 416 amino acids with characteristic cysteine-rich motifs in the extracellular domain and a tumor necrosis factor receptor-associated factor (TRAF) 2 binding sequence in the cytoplasmic domain of 223 amino acids. In fact, activation of nuclear factor kappaB was induced by the overexpression of TROY and inhibited by dominant negative forms of TRAF2, TRAF5, and TRAF6, indicating that TRAFs and nuclear factor kappaB are involved in the signal transduction of TROY. We also cloned a cDNA for a human counterpart, which showed a 75% homology with mouse TROY at the amino acid level. The extracellular domain of TROY exhibits an extensive homology with that of Edar, a receptor that specifies hair follicle fate. TROY mRNA is strongly expressed in brain and embryo and moderately expressed in the heart, lung, and liver but not the spleen. In the embryo, the expression level is particularly strong in the skin. Interestingly, in situ hybridization analysis of the embryo showed that TROY mRNA was exclusively expressed in the epithelium of many tissues. On the other hand, in neonatal mice, TROY is expressed in hair follicles like Edar as well as in the cerebrum, suggesting pleiotropic functions of TROY in development as well as in the adult mice. The Troy gene is located near the waved coat (Wc) locus, a mutant related to abnormalities in skin and hair.

Amino Acid Sequence↗

PubMed2026

Contrasting signals of selection at the EDAR gene in global and Latin American populations.

The EDAR gene is a classic target of positive selection in humans, mainly through the nonsynonymous variant rs3827760 (EDARV370A) associated with ectodermal traits. Using high-resolution data from the 1000 Genomes Project, we combined sliding-window F_ST, BayeScan, and extended haplotype homozygosity (EHH) analyses to examine global and Latin American patterns of differentiation. Globally, a strong signal of positive selection was confirmed at EDAR, dominated by the rs3827760 haplotype background and its extended linkage disequilibrium structure. In contrast, within Latin America, differentiation reflected admixture-driven haplotype persistence rather than contemporary selection. A genome-wide FST scan comparing individuals from the upper and lower quartiles of Native American ancestry showed that EDAR lies among the most highly differentiated regions in this contrast, consistent with ancestry-driven haplotype structure rather than post-admixture adaptive evolution. These results indicate that EDAR retains its evolutionary signature globally but not within recently admixed populations, where demographic history rather than selection shapes its genetic landscape.

Humans↗