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1.
PLoS Biol ; 17(2): e3000064, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30730874

RESUMO

When patterns are set during embryogenesis, it is expected that they are straightly established rather than subsequently modified. The patterning of the three mouse molars is, however, far from straight, likely as a result of mouse evolutionary history. The first-formed tooth signaling centers, called MS and R2, disappear before driving tooth formation and are thought to be vestiges of the premolars found in mouse ancestors. Moreover, the mature signaling center of the first molar (M1) is formed from the fusion of two signaling centers (R2 and early M1). Here, we report that broad activation of Edar expression precedes its spatial restriction to tooth signaling centers. This reveals a hidden two-step patterning process for tooth signaling centers, which was modeled with a single activator-inhibitor pair subject to reaction-diffusion (RD). The study of Edar expression also unveiled successive phases of signaling center formation, erasing, recovering, and fusion. Our model, in which R2 signaling center is not intrinsically defective but erased by the broad activation preceding M1 signaling center formation, predicted the surprising rescue of R2 in Edar mutant mice, where activation is reduced. The importance of this R2-M1 interaction was confirmed by ex vivo cultures showing that R2 is capable of forming a tooth. Finally, by introducing chemotaxis as a secondary process to RD, we recapitulated in silico different conditions in which R2 and M1 centers fuse or not. In conclusion, pattern formation in the mouse molar field relies on basic mechanisms whose dynamics produce embryonic patterns that are plastic objects rather than fixed end points.


Assuntos
Padronização Corporal , Receptor Edar/metabolismo , Modelos Biológicos , Transdução de Sinais , Dente/embriologia , Dente/metabolismo , Animais , Quimiotaxia , Receptor Edar/genética , Epitélio/embriologia , Epitélio/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Cabelo/embriologia , Camundongos , Camundongos Mutantes , Germe de Dente/embriologia , Germe de Dente/metabolismo
2.
PLoS Biol ; 17(2): e3000132, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30789897

RESUMO

Feathers are arranged in a precise pattern in avian skin. They first arise during development in a row along the dorsal midline, with rows of new feather buds added sequentially in a spreading wave. We show that the patterning of feathers relies on coupled fibroblast growth factor (FGF) and bone morphogenetic protein (BMP) signalling together with mesenchymal cell movement, acting in a coordinated reaction-diffusion-taxis system. This periodic patterning system is partly mechanochemical, with mechanical-chemical integration occurring through a positive feedback loop centred on FGF20, which induces cell aggregation, mechanically compressing the epidermis to rapidly intensify FGF20 expression. The travelling wave of feather formation is imposed by expanding expression of Ectodysplasin A (EDA), which initiates the expression of FGF20. The EDA wave spreads across a mesenchymal cell density gradient, triggering pattern formation by lowering the threshold of mesenchymal cells required to begin to form a feather bud. These waves, and the precise arrangement of feather primordia, are lost in the flightless emu and ostrich, though via different developmental routes. The ostrich retains the tract arrangement characteristic of birds in general but lays down feather primordia without a wave, akin to the process of hair follicle formation in mammalian embryos. The embryonic emu skin lacks sufficient cells to enact feather formation, causing failure of tract formation, and instead the entire skin gains feather primordia through a later process. This work shows that a reaction-diffusion-taxis system, integrated with mechanical processes, generates the feather array. In flighted birds, the key role of the EDA/Ectodysplasin A receptor (EDAR) pathway in vertebrate skin patterning has been recast to activate this process in a quasi-1-dimensional manner, imposing highly ordered pattern formation.


Assuntos
Padronização Corporal , Plumas/citologia , Plumas/embriologia , Transdução de Sinais , Animais , Fenômenos Biomecânicos , Aves/embriologia , Agregação Celular , Contagem de Células , Movimento Celular , Forma Celular , Ectodisplasinas/metabolismo , Receptor Edar/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Voo Animal/fisiologia , Mesoderma/citologia , Mesoderma/embriologia , Pele/citologia , Pele/embriologia , beta Catenina/metabolismo
3.
Proc Natl Acad Sci U S A ; 115(19): E4426-E4432, 2018 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-29686092

RESUMO

Because of the ubiquitous adaptability of our material culture, some human populations have occupied extreme environments that intensified selection on existing genomic variation. By 32,000 years ago, people were living in Arctic Beringia, and during the Last Glacial Maximum (LGM; 28,000-18,000 y ago), they likely persisted in the Beringian refugium. Such high latitudes provide only very low levels of UV radiation, and can thereby lead to dangerously low levels of biosynthesized vitamin D. The physiological effects of vitamin D deficiency range from reduced dietary absorption of calcium to a compromised immune system and modified adipose tissue function. The ectodysplasin A receptor (EDAR) gene has a range of pleiotropic effects, including sweat gland density, incisor shoveling, and mammary gland ductal branching. The frequency of the human-specific EDAR V370A allele appears to be uniquely elevated in North and East Asian and New World populations due to a bout of positive selection likely to have occurred circa 20,000 y ago. The dental pleiotropic effects of this allele suggest an even higher occurrence among indigenous people in the Western Hemisphere before European colonization. We hypothesize that selection on EDAR V370A occurred in the Beringian refugium because it increases mammary ductal branching, and thereby may amplify the transfer of critical nutrients in vitamin D-deficient conditions to infants via mothers' milk. This hypothesized selective context for EDAR V370A was likely intertwined with selection on the fatty acid desaturase (FADS) gene cluster because it is known to modulate lipid profiles transmitted to milk from a vitamin D-rich diet high in omega-3 fatty acids.


Assuntos
Clima Frio , Receptor Edar , Ácidos Graxos/metabolismo , Troca Materno-Fetal/fisiologia , Leite Humano/metabolismo , Seleção Genética/fisiologia , Vitamina D/metabolismo , Alelos , Receptor Edar/genética , Receptor Edar/metabolismo , Feminino , Humanos , Masculino , Glândulas Mamárias Humanas/anatomia & histologia , Glândulas Mamárias Humanas/metabolismo , Gravidez
4.
Proc Natl Acad Sci U S A ; 115(32): 8173-8178, 2018 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-30037996

RESUMO

Ectodysplasin A (Eda) signaling activates NF-κB during skin appendage formation, but how Eda controls specific gene transcription remains unclear. Here, we find that Eda triggers the formation of an NF-κB-associated SWI/SNF (BAF) complex in which p50/RelB recruits a linker protein, Tfg, that interacts with BAF45d in the BAF complex. We further reveal that Tfg is initially induced by Eda-mediated RelB activation and then bridges RelB and BAF for subsequent gene regulation. The BAF component BAF250a is particularly up-regulated in skin appendages, and epidermal knockout of BAF250a impairs skin appendage development, resulting in phenotypes similar to those of Eda-deficient mouse models. Transcription profiling identifies several target genes regulated by Eda, RelB, and BAF. Notably, RelB and the BAF complex are indispensable for transcription of Eda target genes, and both BAF complex and Eda signaling are required to open chromatin of Eda targets. Our studies thus suggest that Eda initiates a signaling cascade and recruits a BAF complex to specific gene loci to facilitate transcription during organogenesis.


Assuntos
Proteínas Cromossômicas não Histona/fisiologia , Ectodisplasinas/metabolismo , Organogênese/genética , Pele/embriologia , Fator de Transcrição RelB/genética , Fatores de Transcrição/fisiologia , Transcrição Gênica/fisiologia , Animais , Cromatina/metabolismo , Ectodisplasinas/genética , Receptor Edar/genética , Receptor Edar/metabolismo , Feminino , Perfilação da Expressão Gênica , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NF-kappa B/metabolismo , Proteínas/genética , Proteínas/metabolismo , RNA Interferente Pequeno/metabolismo , Transdução de Sinais/fisiologia , Fator de Transcrição RelB/metabolismo , Ativação Transcricional/fisiologia , Regulação para Cima
5.
Genes Dev ; 27(4): 450-8, 2013 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-23431057

RESUMO

In hair follicle development, a placode-derived signal is believed to induce formation of the dermal condensation, an essential component of ectodermal organs. However, the identity of this signal is unknown. Furthermore, although induction and patterning of hair follicles are intimately linked, it is not known whether the mesenchymal condensation is necessary for inducing the initial epithelial pattern. Here, we show that fibroblast growth factor 20 (Fgf20) is expressed in hair placodes and is induced by and functions downstream from epithelial ectodysplasin (Eda)/Edar and Wnt/ß-Catenin signaling to initiate formation of the underlying dermal condensation. Fgf20 governs formation of primary and secondary dermal condensations in developing hair follicles and subsequent formation of guard, awl, and auchene hairs. Although primary dermal condensations are absent in Fgf20 mutant mice, a regular array of hair placodes is formed, demonstrating that the epithelial patterning process is independent of known histological and molecular markers of underlying mesenchymal patterns during the initial stages of hair follicle development.


Assuntos
Fatores de Crescimento de Fibroblastos/metabolismo , Folículo Piloso/embriologia , Animais , Ectodisplasinas/metabolismo , Receptor Edar/metabolismo , Fatores de Crescimento de Fibroblastos/genética , Regulação da Expressão Gênica no Desenvolvimento , Proteínas Hedgehog/metabolismo , Camundongos , Transdução de Sinais , Proteínas Wnt/metabolismo , beta Catenina/metabolismo
6.
Int J Mol Sci ; 20(21)2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31652981

RESUMO

The dental abnormalities are the typical features of many ectodermal dysplasias along with congenital malformations of nails, skin, hair, and sweat glands. However, several reports of non-syndromic/isolated tooth agenesis have also been found in the literature. The characteristic features of hypohidrotic ectodermal dysplasia (HED) comprise of hypodontia/oligodontia, along with hypohidrosis/anhidrosis, and hypotrichosis. Pathogenic variants in EDA, EDAR, EDARADD, and TRAF6, cause the phenotypic expression of HED. Genetic alterations in EDA and WNT10A cause particularly non-syndromic/isolated oligodontia. In the current project, we recruited 57 patients of 17 genetic pedigrees (A-Q) from different geographic regions of the world, including Pakistan, Egypt, Saudi Arabia, and Syria. The molecular investigation of different syndromic and non-syndromic dental conditions, including hypodontia, oligodontia, generalized odontodysplasia, and dental crowding was carried out by using exome and Sanger sequencing. We have identified a novel missense variant (c.311G>A; p.Arg104His) in WNT10A in three oligodontia patients of family A, two novel sequence variants (c.207delinsTT, p.Gly70Trpfs*25 and c.1300T>G; p.Try434Gly) in EDAR in three patients of family B and four patients of family C, respectively. To better understand the structural and functional consequences of missense variants in WNT10A and EDAR on the stability of the proteins, we have performed extensive molecular dynamic (MD) simulations. We have also identified three previously reported pathogenic variants (c.1076T>C; p.Met359Thr), (c.1133C>T; p.Thr378Met) and (c.594_595insC; Gly201Argfs*39) in EDA in family D (four patients), E (two patients) and F (one patient), correspondingly. Presently, our data explain the genetic cause of 18 syndromic and non-syndromic tooth agenesis patients in six autosomal recessive and X-linked pedigrees (A-F), which expand the mutational spectrum of these unique clinical manifestations.


Assuntos
Displasia Ectodérmica Anidrótica Tipo 1/patologia , Ectodisplasinas/genética , Receptor Edar/genética , Simulação de Dinâmica Molecular , Proteínas Wnt/genética , Displasia Ectodérmica Anidrótica Tipo 1/genética , Ectodisplasinas/química , Ectodisplasinas/metabolismo , Receptor Edar/química , Receptor Edar/metabolismo , Humanos , Mutação de Sentido Incorreto , Linhagem , Fenótipo , Estabilidade Proteica , Estrutura Terciária de Proteína , Sequenciamento do Exoma , Proteínas Wnt/química , Proteínas Wnt/metabolismo
7.
Semin Immunol ; 26(3): 220-8, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24928340

RESUMO

Ectodysplasin (Eda) is the most studied tumor necrosis ligand in the field of developmental biology. In all vertebrates studied so far, inactivating germline mutations in Eda lead to the genetic disease called hypohidrotic ectodermal dysplasia (HED). In humans, HED is a life-threatening condition in particular in infants due to absent or severely reduced sweating leading to hyperthermia. HED is also characterized by sparse hair, and oligo- or anodontia. Research of the Eda pathway has not only increased our knowledge on ectodermal appendage development and etiology of developmental disorders, but also on evolution of several vertebrate species including humankind. Studies on mouse and dog models of HED has led to one of the most stunning breakthroughs in applied developmental biology research by showing that a short-term treatment of neonates with a synthetic ligand corrects many of the HED-associated traits. Eighteen years after the identification of EDA as the causative gene in HED, a phase II trial aiming at permanent correction of the disease is now ongoing. This review summarizes the latest discoveries in the Eda field and points to areas that need further investigation such as the possible involvement of Eda in cell migration, stem cell maintenance, or cancer.


Assuntos
Ectodisplasinas/metabolismo , Receptor Edar/metabolismo , Animais , Displasia Ectodérmica Anidrótica Tipo 1/genética , Displasia Ectodérmica Anidrótica Tipo 1/metabolismo , Ectodisplasinas/genética , Humanos , Transdução de Sinais
8.
Yi Chuan ; 40(11): 1024-1032, 2018 Nov 20.
Artigo em Zh | MEDLINE | ID: mdl-30465535

RESUMO

The ectodysplasinA receptor gene (EDAR) plays an important role in the development of ectoderm. The derived G allele of its key missense variant EDARV370A is prevalent in East Asians and Americans, but rare in Africans and Europeans. This leads to distinct ectodermal-derived phenotypes between different continental groups, such as the straighter and thicker hair, more eccrine sweat glands, feminine smaller breasts, shovel incisors characteristic of East Asians. At present, we know little about the association between EDARV370A and facial and ear morphology characteristics. To better understand the effect of EDARV370A on craniofacial phenotypes, we systematically examined the association between EDARV370A and 136 facial quantitative phenotypes, one chin ordinal phenotype and six ear ordinal phenotypes in 715 Uyghurs. The quantitative phenotypes were derived by applying our automated landmark annotation method to facial 3D photos and the ordinal phenotypes were manually graded from facial 2D photos. The analysis identified significant association (P<0.05 after multiple testing correction) between EDARV370A and eight facial phenotypes, one chin phenotype and three ear morphology phenotypes. Our study thus elucidated the pleotropic effect of EDARV370A on craniofacial phenotypes in a European-Asian admixed Uyghur population.


Assuntos
Povo Asiático/genética , Orelha/anatomia & histologia , Receptor Edar/genética , Face/anatomia & histologia , Mutação de Sentido Incorreto , Adolescente , Adulto , Alelos , Povo Asiático/etnologia , China/etnologia , Orelha/crescimento & desenvolvimento , Receptor Edar/metabolismo , Feminino , Humanos , Masculino , Desenvolvimento Maxilofacial , Pessoa de Meia-Idade , Fenótipo , Adulto Jovem
9.
Trends Genet ; 30(1): 24-31, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24070496

RESUMO

The ectodysplasin (EDA) pathway, which is active during the development of ectodermal organs, including teeth, hairs, feathers, and mammary glands, and which is crucial for fine-tuning the developmental network controlling the number, size, and density of these structures, was discovered by studying human patients affected by anhidrotic/hypohidrotic ectodermal dysplasia. It comprises three main gene products: EDA, a ligand that belongs to the tumor necrosis factor (TNF)-α family, EDAR, a receptor related to the TNFα receptors, and EDARADD, a specific adaptor. This core pathway relies on downstream NF-κB pathway activation to regulate target genes. The pathway has recently been found to be associated with specific adaptations in natural populations: the magnitude of armor plates in sticklebacks and the hair structure in Asian human populations. Thus, despite its role in human disease, the EDA pathway is a 'hopeful pathway' that could allow adaptive changes in ectodermal appendages which, as specialized interfaces with the environment, are considered hot-spots of morphological evolution.


Assuntos
Adaptação Fisiológica/genética , Displasia Ectodérmica Anidrótica Tipo 1/genética , Ectodisplasinas/genética , Animais , Ectodisplasinas/metabolismo , Receptor Edar/genética , Receptor Edar/metabolismo , Proteína de Domínio de Morte Associada a Edar/genética , Proteína de Domínio de Morte Associada a Edar/metabolismo , Regulação da Expressão Gênica , Humanos , NF-kappa B/genética , NF-kappa B/metabolismo , Receptores do Fator de Necrose Tumoral/genética , Receptores do Fator de Necrose Tumoral/metabolismo , Transdução de Sinais , Vertebrados/genética
10.
Clin Exp Immunol ; 184(2): 183-96, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26724675

RESUMO

Sjögren's syndrome (SS) is an autoimmune disease and the second most common chronic systemic rheumatic disorder. Prevalence of primary SS in the general population has been estimated to be approximately 1-3%, whereas secondary SS has been observed in 10-20% of patients with rheumatoid arthritis, systemic lupus erythematosus (SLE) and scleroderma. Despite this, its exact aetiology and pathogenesis are largely unexplored. Nuclear factor-kappa B (NF-κB) signalling mechanisms provide central controls in SS, but how these pathways intersect the pathological features of this disease is unclear. The ubiquitin-editing enzyme A20 (tumour necrosis factor-α-induced protein 3, TNFAIP3) serves as a critical inhibitor on NF-κB signalling. In humans, polymorphisms in the A20 gene or a deregulated expression of A20 are often associated with several inflammatory disorders, including SS. Because A20 controls the ectodysplasin-A1 (EDA-A1)/ectodysplasin receptor (EDAR) signalling negatively, and the deletion of A20 results in excessive EDA1-induced NF-κB signalling, this work investigates the expression levels of EDA-A1 and EDAR in SS human salivary glands epithelial cells (SGEC) and evaluates the hypothesis that SS SGEC-specific deregulation of A20 results in excessive EDA1-induced NF-κB signalling in SS. Our approach, which combines the use of siRNA-mediated gene silencing and quantitative pathway analysis, was used to elucidate the role of the A20 target gene in intracellular EDA-A1/EDAR/NF-κB pathway in SS SGEC, holding significant promise for compound selection in drug discovery.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Ectodisplasinas/metabolismo , Receptor Edar/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , NF-kappa B/metabolismo , Proteínas Nucleares/metabolismo , Síndrome de Sjogren/patologia , Proteínas de Ligação a DNA/genética , Células Epiteliais/metabolismo , Humanos , Proteínas I-kappa B/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Inibidor de NF-kappaB alfa , Proteínas Nucleares/genética , Interferência de RNA , RNA Interferente Pequeno/genética , Glândulas Salivares/citologia , Glândulas Salivares/metabolismo , Transdução de Sinais , Proteína 3 Induzida por Fator de Necrose Tumoral alfa
11.
Am J Med Genet A ; 170A(1): 249-53, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26440664

RESUMO

Hypohidrotic ectodermal dysplasia (HED) is a rare disorder characterized by deficient development of structures derived from the ectoderm including hair, nails, eccrine glands, and teeth. HED forms that are caused by mutations in the genes EDA, EDAR, or EDARADD may show almost identical phenotypes, explained by a common signaling pathway. Proper interaction of the proteins encoded by these three genes is important for the activation of the NF-κB signaling pathway and subsequent transcription of the target genes. Mutations in the gene EDARADD are most rarely implicated in HED. Here we describe a novel missense mutation, c.367G>A (p.Asp123Asn), in this gene which did not appear to influence the interaction between EDAR and EDARADD proteins, but led to an impaired ability to activate NF-κB signaling. Female members of the affected family showed either unilateral or bilateral amazia. In addition, an affected girl developed bilateral ovarian teratomas, possibly associated with her genetic condition.


Assuntos
Displasia Ectodérmica Anidrótica Tipo 1/genética , Receptor Edar/genética , Proteína de Domínio de Morte Associada a Edar/genética , Mutação de Sentido Incorreto/genética , Neoplasias Ovarianas/genética , Teratoma/genética , Adolescente , Doenças Mamárias/genética , Receptor Edar/metabolismo , Proteína de Domínio de Morte Associada a Edar/metabolismo , Feminino , Cabelo/crescimento & desenvolvimento , Humanos , Masculino , NF-kappa B/metabolismo , Neoplasias Ovarianas/patologia , Linhagem , Transdução de Sinais/genética , Teratoma/patologia
12.
Histochem Cell Biol ; 143(5): 481-96, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25366125

RESUMO

Mice with skin and hair follicle (HF) defects are common models of human skin disorders. A mutant strain with the we/we wal/wal genotype develops alopecia. We found the hair shaft structure in the pelage of mutant mice to have significant defects. Although these mice lose their hair at 21 days, a label-retaining cell population persists in HFs until at least day 54. Depilation-induced anagen was accomplished in we/we wal/wal mutants but the resulting hair shafts were short and extremely deformed. Serious abnormalities in epidermis stratification and HF morphogenesis exist in we/we wal/wal homozygous E18.5 embryos. There were significantly fewer HF primordia in this mutant compared with wild type. We discovered specific structures, identified as invalid placodes, positive for ectodysplasin A1 receptor, nuclear ß-catenin, and LEF1, which failed to invaginate, produced a double basal-like layer of epidermal cells, and lacked cylindrical keratinocytes. Specification of dermal papillae (DP) was impaired, and the papillary dermis expressed alkaline phosphatase and LEF1. We also detected DP-like groups of intensively stained cells in the absence of visible signs of folliculogenesis in the epidermis. We showed differentiation disturbances in the mutant embryonic E18.5 epidermis and HFs: The cornified layer was absent, the width of the spinous layer was reduced, and HFs lacked LEF1-positive precortex cells. In this study, we used a very interesting and useful mouse model of alopecia. The presence of symptoms of skin disorders in we/we wal/wal murine embryos correlates with the postnatal skin phenotype. This correlation may help to evaluate reasons of alopecia.


Assuntos
Alopecia/patologia , Epiderme/anormalidades , Folículo Piloso/anormalidades , Fatores Etários , Alopecia/embriologia , Alopecia/genética , Alopecia/metabolismo , Animais , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Modelos Animais de Doenças , Receptor Edar/metabolismo , Epiderme/metabolismo , Genótipo , Idade Gestacional , Folículo Piloso/metabolismo , Remoção de Cabelo , Queratinócitos/metabolismo , Queratinócitos/patologia , Fator 1 de Ligação ao Facilitador Linfoide/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Morfogênese , Fenótipo , beta Catenina/metabolismo
13.
Dev Dyn ; 243(6): 765-77, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24585696

RESUMO

BACKGROUND: Ectodysplasin (Eda) signaling is essential for the morphogenesis of several ectodermal appendages. RESULTS: Here, we report a medaka mutant, all-fin less (afl), which has a nonsense mutation in its eda gene. The adult afl fish displayed various abnormalities of its dermal skeleton, such as short and twisted fin rays, missing and abnormally shaped scales and teeth, and skull deformation. Focusing on the developing fin rays in the caudal region of afl larvae, we found that the fin rays did not elongate; although the initial formation of fin rays proceeded normally. Additionally, eda expression was lost, and the expression pattern of edar, the gene for the receptor of Eda, was different from wild-type one. In vivo imaging of the double-transgenic medaka expressing enhanced green fluorescent protein under control of the edar promoter and DsRed under control of the osterix promoter revealed that edar expression preceded that of osterix and that the edar-expressing cells migrated in the direction of fin ray elongation, indicating that the Eda/Edar signaling event precedes osteoblast differentiation. CONCLUSIONS: Our findings provide evidence that Eda signaling accompanied with the binding of Eda to Edar are essential for fin ray formation guided by cell migration.


Assuntos
Nadadeiras de Animais/embriologia , Diferenciação Celular/fisiologia , Ectodisplasinas/metabolismo , Receptor Edar/metabolismo , Proteínas de Peixes/metabolismo , Oryzias/embriologia , Osteoblastos/metabolismo , Transdução de Sinais/fisiologia , Nadadeiras de Animais/citologia , Animais , Ectodisplasinas/genética , Receptor Edar/genética , Proteínas de Peixes/genética , Oryzias/genética , Osteoblastos/citologia
14.
Trends Cell Biol ; 34(5): 360-362, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38461099

RESUMO

Mutations and polymorphisms in A20/TNFAIP3 have been linked to various inflammatory disorders. However, in addition to its well-known role in inflammation, A20 also controls EDAR- and receptor activator of NF-κB (RANK)-induced NF-κB signaling, regulating the development of epidermal skin appendages and bone, respectively. Furthermore, A20 regulates synapse remodeling through a mechanism dependent on NF-κB.


Assuntos
NF-kappa B , Transdução de Sinais , Proteína 3 Induzida por Fator de Necrose Tumoral alfa , Animais , Humanos , Receptor Edar/metabolismo , Inflamação/metabolismo , Inflamação/patologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , NF-kappa B/metabolismo , Receptor Ativador de Fator Nuclear kappa-B/metabolismo , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/metabolismo
15.
Evol Dev ; 15(6): 393-405, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24261441

RESUMO

Few skeletal structures are as informative of the adaptive natural history of vertebrate animals as their teeth. Understanding principles of tooth development is key to understanding evolution of the vertebrate dentition in general and emergence of multiple specialized tooth types in particular. Morphological and phylogenetic considerations suggest that crocodilians have the most primitive mode of dentition within extant tetrapods, displaying simple, conical, socketed, and continuously replaced teeth. Previous histological studies revealed several dental fates, including functional and non-functional teeth (rudiments) in the developing alligator embryos. We analyze expression of key odontogenic regulators and markers to better characterize the molecular patterning of crocodilian dentition. Importantly, we demonstrate that the morphologically distinct tooth types in Alligator mississippiensis are distinguishable by differences in their developmental programs. We also present evidence showing that tooth maturation is accompanied by dynamic gene expression in the epithelial and mesenchymal cells involved in tooth development. Our data reveal a significant morphological and genetic variation in early dental fates. We believe that this underlying developmental variation reflects modularity, or the ability of teeth to develop semi-autonomously along the alligator jaw. We propose that such modularity may have been a crucial for adaptive evolution within Amniota, allowing for the progressive modifications to tooth replacement, number, and shape.


Assuntos
Jacarés e Crocodilos/crescimento & desenvolvimento , Evolução Biológica , Dente/crescimento & desenvolvimento , Jacarés e Crocodilos/anatomia & histologia , Jacarés e Crocodilos/genética , Jacarés e Crocodilos/fisiologia , Animais , Receptor Edar/genética , Receptor Edar/metabolismo , Fator 4 de Crescimento de Fibroblastos/genética , Regulação da Expressão Gênica no Desenvolvimento , Proteínas Hedgehog/genética , Organogênese , Dente/anatomia & histologia , Dente/metabolismo
16.
Br J Dermatol ; 168(3): 629-33, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22924441

RESUMO

BACKGROUND: Hypohidrotic ectodermal dysplasia (HED) is a rare condition characterized by hypotrichosis, hypohidrosis and hypodontia. A de novo heterozygous mutation in the tumour necrosis factor receptor-associated factor 6 gene (TRAF6) was recently identified in a patient with HED, while functional consequences resulting from the mutation remained unknown. OBJECTIVES: To determine the mechanism by which the TRAF6 mutation results in HED. METHODS: We performed coimmunoprecipitation (co-IP) studies to determine whether the mutation would affect the interaction of TRAF6 with transforming growth factor ß-activated kinase 1 (TAK1), TAK1-binding protein 2 (TAB 2) and ectodysplasin-A receptor-associated death domain protein (EDARADD). We then performed co-IP and glutathione S-transferase-pulldown assays to determine the TRAF6 binding sequences in EDARADD. In addition, we analysed the effect of the mutant TRAF6 protein on the affinity between wild-type TRAF6 and EDARADD, as well as on EDARADD-mediated nuclear factor (NF)-κB activation. RESULTS: The mutant TRAF6 protein was capable of forming a complex with TAK1 and TAB 2 in a similar way to wild-type TRAF6. However, the mutant TRAF6 protein completely lost the affinity to EDARADD, while the wild-type TRAF6 bound to the N-terminal domain of EDARADD. Furthermore, the mutant TRAF6 inhibited the interaction between the wild-type TRAF6 and EDARADD, and also potentially reduced the EDARADD-mediated NF-κB activity. CONCLUSIONS: We conclude that the mutant TRAF6 protein shows a dominant negative effect against the wild-type TRAF6 protein, which is predicted to affect the EDARADD-mediated activation of NF-κB during the development of ectoderm-derived organs, and to lead to the HED phenotype.


Assuntos
Displasia Ectodérmica Hipo-Hidrótica Autossômica Recessiva/genética , Mutação/genética , Fator 6 Associado a Receptor de TNF/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Interações Medicamentosas , Receptor Edar/genética , Receptor Edar/metabolismo , Proteína de Domínio de Morte Associada a Edar/genética , Proteína de Domínio de Morte Associada a Edar/metabolismo , Humanos , Imunoprecipitação , NF-kappa B/metabolismo , Fator 6 Associado a Receptor de TNF/metabolismo
17.
Differentiation ; 84(3): 232-9, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22898663

RESUMO

The purpose of this study was to validate a combined in situ hybridization (ISH)/immunohistochemistry (IHC) staining method for visualizing and quantifying mouse prostatic buds. To refine animal usage in prostate development studies, we also determined whether a comparable number of prostatic buds were formed in male and female mouse urogenital sinus (UGS) explants grown in vitro in the presence of androgen. We used IHC to label UGS epithelium and ISH to label prostatic buds with one of three different prostatic bud marking riboprobes: a previously identified prostatic bud marker, NK-3 transcription factor, locus 1 (Nkx3-1), and two newly identified prostatic bud markers, wingless-related MMTV integration site 10b (Wnt10b) and ectodysplasin-A receptor (Edar). We calculated total buds formed per UGS and the proportion marked by each mRNA after male UGS development in vivo and male and female UGS development in vitro. Nkx3-1 was first to mark the prostate field during UGS development in vivo but all three mRNAs marked prostatic buds during later developmental stages. The mRNAs localized to different domains: Nkx3-1 was present along about half the prostatic bud length while Edar and Wnt10b were restricted to distal bud tips. None of the mRNAs marked all buds formed in vitro and the proportion marked was developmental stage- and gender-dependent. Nkx3-1 marked the highest proportion of prostatic buds during in vitro UGS development. Together, our results reveal that ISH staining of mouse UGS can be used to quantify prostatic bud number, Nkx3-1 is currently the best suited riboprobe for this method, and female UGSs cannot be used interchangeably with male UGSs when conducting prostate development studies in vitro. We also found that Nkx3-1, Edar, and Wnt10b mark different prostatic bud regions and are likely to be useful in future studies of regional differences in prostatic bud gene expression.


Assuntos
Hibridização In Situ/métodos , Próstata/embriologia , Animais , Receptor Edar/genética , Receptor Edar/metabolismo , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Imuno-Histoquímica , Técnicas In Vitro , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Próstata/metabolismo , RNA Mensageiro/biossíntese , Fatores Sexuais , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteínas Wnt/genética , Proteínas Wnt/metabolismo
18.
J Dermatol ; 50(10): 1357-1362, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37269152

RESUMO

Pathogenic variants in the EDARADD gene result in autosomal recessive and autosomal dominant ectodermal dysplasia. This article reports on the fourth family in the world with ectodermal dysplasia 11A (ECTD11A) cause from a novel splicing variant in the EDARADD gene, identified by whole exome sequencing and confirmed by Sanger sequencing. The proband and his mother were heterozygous for the detected variant (NM_145861.4:c.161-2A>T). The proband manifests unusual symptoms including hyperkeratotic plaques, slow-growing hair, recurrent infection, and pectus excavatum. His mother presents hypohidrosis, extensive tooth decay, fragile nails, and sparse hair. Further studies on ECTD11A patients could be useful to characterizing the phenotype features more precisely.


Assuntos
Displasia Ectodérmica , Receptor Edar , Feminino , Humanos , Receptor Edar/genética , Receptor Edar/metabolismo , Linhagem , Displasia Ectodérmica/diagnóstico , Displasia Ectodérmica/genética , Fenótipo , Mães , Proteína de Domínio de Morte Associada a Edar/genética
19.
J Dermatol ; 50(3): 349-356, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36258277

RESUMO

Hypohidrotic ectodermal dysplasia is a rare condition characterized by hypohidrosis, hypodontia, and hypotrichosis. The disease can show X-linked recessive, autosomal dominant or autosomal recessive inheritance trait. Of these, the autosomal forms are caused by mutations in either EDAR or EDARADD. To date, the underlying pathomechanisms or genotype-phenotype correlations for autosomal forms have not completely been disclosed. In this study, we performed a series of in vitro studies for four missense mutations in the death domain of EDAR protein: p.R358Q, p.G382S, p.I388T, and p.T403M. The results revealed that p.R358Q- and p.T403M-mutant EDAR showed different expression patterns from wild-type EDAR in both western blots and immunostainings. NF-κB reporter assays demonstrated that all the mutant EDAR showed reduced activation of NF-κB, but the reduction by p.G382S- and p.I388T-mutant EDAR was moderate. Co-immunoprecipitation assays showed that p.R358Q- and p.T403M-mutant EDAR did not bind with EDARADD at all, whereas p.G382S- and p.I388T-mutant EDAR maintained the affinity to some extent. Furthermore, we demonstrated that all the mutant EDAR proteins analyzed aberrantly bound with TRAF6. Sum of the data suggest that the degree of loss-of-function is different among the mutant EDAR proteins, which may be associated with the severity of the disease.


Assuntos
Displasia Ectodérmica Anidrótica Tipo 1 , Displasia Ectodérmica , Humanos , Mutação de Sentido Incorreto , Displasia Ectodérmica Anidrótica Tipo 1/diagnóstico , Displasia Ectodérmica Anidrótica Tipo 1/genética , NF-kappa B/genética , NF-kappa B/metabolismo , Receptor Edar/genética , Receptor Edar/metabolismo , Displasia Ectodérmica/genética , Mutação
20.
PLoS Genet ; 4(10): e1000206, 2008 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-18833299

RESUMO

The genetic basis of the development and variation of adult form of vertebrates is not well understood. To address this problem, we performed a mutant screen to identify genes essential for the formation of adult skeletal structures of the zebrafish. Here, we describe the phenotypic and molecular characterization of a set of mutants showing loss of adult structures of the dermal skeleton, such as the rays of the fins and the scales, as well as the pharyngeal teeth. The mutations represent adult-viable, loss of function alleles in the ectodysplasin (eda) and ectodysplasin receptor (edar) genes. These genes are frequently mutated in the human hereditary disease hypohidrotic ectodermal dysplasia (HED; OMIM 224900, 305100) that affects the development of integumentary appendages such as hair and teeth. We find mutations in zebrafish edar that affect similar residues as mutated in human cases of HED and show similar phenotypic consequences. eda and edar are not required for early zebrafish development, but are rather specific for the development of adult skeletal and dental structures. We find that the defects of the fins and scales are due to the role of Eda signaling in organizing epidermal cells into discrete signaling centers of the scale epidermal placode and fin fold. Our genetic analysis demonstrates dose-sensitive and organ-specific response to alteration in levels of Eda signaling. In addition, we show substantial buffering of the effect of loss of edar function in different genetic backgrounds, suggesting canalization of this developmental system. We uncover a previously unknown role of Eda signaling in teleosts and show conservation of the developmental mechanisms involved in the formation and variation of both integumentary appendages and limbs. Lastly, our findings point to the utility of adult genetic screens in the zebrafish in identifying essential developmental processes involved in human disease and in morphological evolution.


Assuntos
Displasia Ectodérmica/metabolismo , Ectodisplasinas/metabolismo , Receptor Edar/metabolismo , Evolução Molecular , Mutação , Transdução de Sinais , Proteínas de Peixe-Zebra/metabolismo , Peixe-Zebra/crescimento & desenvolvimento , Animais , Padronização Corporal , Displasia Ectodérmica/genética , Ectodisplasinas/genética , Receptor Edar/genética , Epiderme/crescimento & desenvolvimento , Epiderme/metabolismo , Humanos , Esqueleto , Vertebrados/genética , Vertebrados/crescimento & desenvolvimento , Vertebrados/metabolismo , Peixe-Zebra/genética , Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/genética
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