RESUMO
Notch signaling regulates a vast array of crucial developmental processes. It is therefore not surprising that mutations in genes encoding Notch receptors or ligands lead to a variety of congenital disorders in humans. For example, loss of function of Notch results in Adams-Oliver syndrome, Alagille syndrome, spondylocostal dysostosis and congenital heart disorders, while Notch gain of function results in Hajdu-Cheney syndrome, serpentine fibula polycystic kidney syndrome, infantile myofibromatosis and lateral meningocele syndrome. Furthermore, structure-abrogating mutations in NOTCH3 result in CADASIL. Here, we discuss these human congenital disorders in the context of known roles for Notch signaling during development. Drawing on recent analyses by the exome aggregation consortium (EXAC) and on recent studies of Notch signaling in model organisms, we further highlight additional Notch receptors or ligands that are likely to be involved in human genetic diseases.
Assuntos
Doenças Genéticas Inatas/embriologia , Doenças Genéticas Inatas/genética , Receptores Notch/genética , Anormalidades Múltiplas/embriologia , Anormalidades Múltiplas/genética , Síndrome de Alagille/embriologia , Síndrome de Alagille/genética , Animais , Biologia do Desenvolvimento , Displasia Ectodérmica/embriologia , Displasia Ectodérmica/genética , Síndrome de Hajdu-Cheney/embriologia , Síndrome de Hajdu-Cheney/genética , Hérnia Diafragmática/embriologia , Hérnia Diafragmática/genética , Humanos , Deformidades Congênitas dos Membros/embriologia , Deformidades Congênitas dos Membros/genética , Meningocele/embriologia , Meningocele/genética , Dermatoses do Couro Cabeludo/congênito , Dermatoses do Couro Cabeludo/embriologia , Dermatoses do Couro Cabeludo/genéticaRESUMO
Costello syndrome (CS) is a RASopathy characterized by a wide range of cardiac, musculoskeletal, dermatological, and developmental abnormalities. The RASopathies are defined as a group of syndromes caused by activated Ras/mitogen-activated protein kinase (MAPK) signaling. Specifically, CS is caused by activating mutations in HRAS. Although receptor tyrosine kinase (RTK) signaling, which is upstream of Ras/MAPK, is known to play a critical role in craniofacial and dental development, the craniofacial and dental features of CS have not been systematically defined in a large group of individuals. In order to address this gap in our understanding and fully characterize the CS phenotype, we evaluated the craniofacial and dental phenotype in a large cohort (n = 41) of CS individuals. We confirmed that the craniofacial features common in CS include macrocephaly, bitemporal narrowing, convex facial profile, full cheeks, and large mouth. Additionally, CS patients have a characteristic dental phenotype that includes malocclusion with anterior open bite and posterior crossbite, enamel hypo-mineralization, delayed tooth development and eruption, gingival hyperplasia, thickening of the alveolar ridge, and high palate. Comparison of the craniofacial and dental phenotype in CS with other RASopathies, such as cardio-facio-cutaneous syndrome (CFC), provides insight into the complexities of Ras/MAPK signaling in human craniofacial and dental development.
Assuntos
Síndrome de Costello/genética , Anormalidades Craniofaciais/embriologia , Anormalidades Craniofaciais/genética , Sistema de Sinalização das MAP Quinases/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Anormalidades Múltiplas/embriologia , Anormalidades Múltiplas/genética , Adolescente , Adulto , Criança , Hipoplasia do Esmalte Dentário/embriologia , Hipoplasia do Esmalte Dentário/genética , Displasia Ectodérmica/embriologia , Displasia Ectodérmica/genética , Fácies , Insuficiência de Crescimento/embriologia , Insuficiência de Crescimento/genética , Feminino , Hiperplasia Gengival/embriologia , Hiperplasia Gengival/genética , Cardiopatias Congênitas/embriologia , Cardiopatias Congênitas/genética , Humanos , Masculino , Má Oclusão/embriologia , Má Oclusão/genética , Proteínas Quinases Ativadas por Mitógeno/genética , Mutação , Fosfatidilinositol 3-Quinases/genética , Dente/embriologia , Anormalidades Dentárias/embriologia , Anormalidades Dentárias/genética , Adulto JovemRESUMO
OBJECTIVE: To analyze GJB6 gene mutations in a Chinese family with hidrotic ectodermal dysplasia and to provide first-trimester prenatal diagnosis for a fetus. METHODS: Mutation scanning was carried out with PCR and bilateral direct sequencing in 2 affected and 6 unaffected individuals from the family. After the mutation was confirmed, prenatal diagnosis was performed on chorionic villi samples obtained at 11th gestational week. RESULTS: A heterozygous missense mutation c.31G>A of the GJB6 gene was discovered in all of the patients, which has led to substitution of glycine by arginine at codon 11 (p.G11R) at the N-terminal of the GJB6 protein. Prenatal diagnosis indicated that the fetus had also carried the same p.G11R mutation. Following termination of the pregnancy, analysis of the aborted tissues was consistent with prenatal diagnosis. CONCLUSION: The missense mutation c.31G>A(p.G11R) of the GJB6 gene probably underlies the disease in this family. Prenatal diagnosis with DNA sequencing can facilitate genetic counseling of this family.
Assuntos
Povo Asiático/genética , Displasia Ectodérmica/diagnóstico , Displasia Ectodérmica/embriologia , Displasia Ectodérmica/genética , Doenças Fetais/diagnóstico , Primeiro Trimestre da Gravidez/genética , Adulto , Sequência de Bases , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Doenças Fetais/genética , Humanos , Masculino , Dados de Sequência Molecular , Linhagem , Gravidez , Diagnóstico Pré-NatalRESUMO
Pyloric atresia is an uncommon congenital gastric outlet obstruction, accounting for only 1% of gastrointestinal atresias. Up to 55% of cases have associated anomalies, the most common of which is epidermolysis bullosa. Fetal MRI findings of the epidermolysis bullosa-pyloric atresia association have not been previously reported. We present a case of this association diagnosed by prenatal MRI with corroborative postnatal imaging and surgical findings.
Assuntos
Displasia Ectodérmica/diagnóstico , Displasia Ectodérmica/embriologia , Obstrução da Saída Gástrica/diagnóstico , Obstrução da Saída Gástrica/embriologia , Imageamento por Ressonância Magnética/métodos , Diagnóstico Pré-Natal/métodos , Piloro/anormalidades , Humanos , Recém-Nascido , Piloro/embriologia , Estatística como AssuntoRESUMO
Las displasias ectodérmicas son un amplio grupo de trastornos hereditarios que se caracterizan por la alteración de estructuras derivadas del ectodermo. Aunque algunos de estos síndromes poseen características específicas, determinados rasgos clínicos son comunes en muchos de ellos. De modo general, se diferencian 2 grupos de trastornos: uno caracterizado por la aplasia o hipoplasia de los derivados ectodérmicos, que fracasan en su desarrollo y diferenciación por la ausencia de señales recíprocas específicas entre ectodermo y mesénquima, y otro en el que la característica más llamativa es la queratodermia palmoplantar, que se presenta en asociación con otras manifestaciones cuando se afectan otros epitelios altamente especializados. En las últimas décadas se ha logrado identificar el gen responsable en al menos 30 entidades, permitiéndonos entender los mecanismos patogénicos y su correlación con la clínica (AU)
The ectodermal dysplasias are a large group of hereditary disorders characterized by alterations of structures of ectodermal origin. Although some syndromes can have specific features, many of them share common clinical characteristics. Two main groups of ectodermal dysplasias can be distinguished. One group is characterized by aplasia or hypoplasia of ectodermal tissues, which fail to develop and differentiate because of a lack of reciprocal signaling between ectoderm and mesoderm, the other has palmoplantar keratoderma as its most striking feature, with additional manifestations when other highly specialized epithelia are also involved. In recent decades, the genes responsible for at least 30 different types of ectodermal dysplasia have been identified, throwing light on the pathogenic mechanisms involved and their correlation with clinical findings (AU)
Assuntos
Humanos , Masculino , Feminino , Displasia Ectodérmica/diagnóstico , Displasia Ectodérmica/genética , Displasia Ectodérmica/fisiopatologia , NF-kappa B/genética , NF-kappa B/fisiologia , Ectodisplasinas/genética , Displasia Ectodérmica/embriologia , Displasia Ectodérmica/classificação , Ectodisplasinas/fisiologia , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/genética , Sindactilia/etiologia , Fissura Palatina , Fenda Labial , Transtornos da PigmentaçãoRESUMO
The ectodermal dysplasias are a group of inherited autosomal dominant syndromes associated with heterozygous mutations in the Tumor Protein p63 (TRP63) gene. Here we show that, in addition to their epidermal pathology, a proportion of these patients have distinct levels of deafness. Accordingly, p63 null mouse embryos show marked cochlea abnormalities, and the transactivating isoform of p63 (TAp63) protein is normally found in the organ of Corti. TAp63 transactivates hairy and enhancer of split 5 (Hes5) and atonal homolog 1 (Atoh1), components of the Notch pathway, known to be involved in cochlear neuroepithelial development. Strikingly, p63 null mice show morphological defects of the organ of Corti, with supernumerary hair cells, as also reported for Hes5 null mice. This phenotype is related to loss of a differentiation property of TAp63 and not to loss of its proapoptotic function, because cochleas in mice lacking the critical Bcl-2 homology domain (BH-3) inducers of p53- and p63-mediated apoptosis--Puma, Noxa, or both--are normal. Collectively, these data demonstrate that TAp63, acting via the Notch pathway, is crucial for the development of the organ of Corti, providing a molecular explanation for the sensorineural deafness in ectodermal dysplasia patients with TRP63 mutations.
Assuntos
Cóclea/embriologia , Cóclea/patologia , Surdez/patologia , Perda Auditiva Neurossensorial/patologia , Fosfoproteínas/metabolismo , Receptores Notch/metabolismo , Transdução de Sinais , Transativadores/metabolismo , Animais , Proteínas Reguladoras de Apoptose/deficiência , Proteínas Reguladoras de Apoptose/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Cóclea/metabolismo , Surdez/embriologia , Surdez/metabolismo , Displasia Ectodérmica/embriologia , Displasia Ectodérmica/genética , Displasia Ectodérmica/patologia , Perda Auditiva Neurossensorial/embriologia , Perda Auditiva Neurossensorial/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosfoproteínas/deficiência , Regiões Promotoras Genéticas/genética , Isoformas de Proteínas/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/deficiência , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas Repressoras/metabolismo , Transativadores/deficiência , Proteínas Supressoras de Tumor/deficiência , Proteínas Supressoras de Tumor/metabolismoRESUMO
Cardio-facio-cutaneous (CFC) syndrome is caused by germline mutations in KRAS, BRAF and MEK1/2. The highly selective and potent MEK inhibitors that have been developed as anti-cancer agents hold potential as therapeutics for CFC syndrome. We have previously shown that the effects of CFC mutations on zebrafish gastrulation can be prevented by a 1-hour treatment with MEK inhibitors within a specific developmental time-window. However, MEK activity is essential for normal development and PD0325901 treatment outside this treatment window leads to additional developmental defects in MEK-dependent tissues. We now test ten different doses of PD0325901 at six developmental time points and assess the effects on body axis length, heart development and craniofacial structures in zebrafish embryos. Notably, we find that a continuous low-level dose of PD0325901 that has only minor inhibition of MEK activity can prevent the action of both the common CFC BRAF(Q257R) kinase-active allele and the BRAF(G596V) kinase-impaired mutant allele through the first 5 days of development. These results provide a detailed study of the effects of PD0325901 in development and show that, unlike in cancer, which requires robust inhibition of MAPK signalling, a partial reduction in phospho-ERK1/2 activity is sufficient to moderate the developmental effects of BRAF(CFC) mutations.
Assuntos
Displasia Ectodérmica/tratamento farmacológico , Displasia Ectodérmica/enzimologia , Insuficiência de Crescimento/tratamento farmacológico , Insuficiência de Crescimento/enzimologia , Cardiopatias Congênitas/tratamento farmacológico , Cardiopatias Congênitas/enzimologia , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Peixe-Zebra/embriologia , Animais , Benzamidas/química , Benzamidas/farmacologia , Benzamidas/uso terapêutico , Difenilamina/análogos & derivados , Difenilamina/química , Difenilamina/farmacologia , Difenilamina/uso terapêutico , Displasia Ectodérmica/embriologia , Displasia Ectodérmica/patologia , Embrião não Mamífero/efeitos dos fármacos , Embrião não Mamífero/metabolismo , Fácies , Insuficiência de Crescimento/embriologia , Insuficiência de Crescimento/patologia , Cardiopatias Congênitas/embriologia , Cardiopatias Congênitas/patologia , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Fenótipo , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas B-raf/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologiaAssuntos
Anormalidades Múltiplas/patologia , Displasia Ectodérmica/patologia , Deformidades Congênitas dos Membros/patologia , Dermatoses do Couro Cabeludo/congênito , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/embriologia , Anormalidades Múltiplas/genética , Adolescente , Vasos Sanguíneos/embriologia , Criança , Consanguinidade , Displasia Ectodérmica/diagnóstico , Displasia Ectodérmica/embriologia , Displasia Ectodérmica/genética , Feminino , Deformidades Congênitas do Pé/genética , Humanos , Deformidades Congênitas dos Membros/diagnóstico , Deformidades Congênitas dos Membros/embriologia , Deformidades Congênitas dos Membros/genética , Masculino , Dermatoses do Couro Cabeludo/diagnóstico , Dermatoses do Couro Cabeludo/embriologia , Dermatoses do Couro Cabeludo/genética , Dermatoses do Couro Cabeludo/patologiaAssuntos
Desenvolvimento Embrionário/genética , Coração Fetal/crescimento & desenvolvimento , Cardiopatias Congênitas/genética , Miócitos Cardíacos/citologia , Fosfoproteínas/fisiologia , Transativadores/fisiologia , Fatores de Transcrição/fisiologia , Proteínas Supressoras de Tumor/fisiologia , Animais , Proteína Morfogenética Óssea 4/fisiologia , Diferenciação Celular , Ectoderma/citologia , Displasia Ectodérmica/embriologia , Displasia Ectodérmica/genética , Epiderme/embriologia , Extremidades/embriologia , Coração Fetal/patologia , Genes Dominantes , Cardiopatias Congênitas/embriologia , Humanos , Queratinócitos/citologia , Camundongos , Morfogênese , Miócitos Cardíacos/metabolismo , Fenótipo , Fosfoproteínas/deficiência , Fosfoproteínas/genética , Isoformas de Proteínas/fisiologia , Transativadores/deficiência , Transativadores/genética , Fatores de Transcrição/deficiência , Fatores de Transcrição/genética , Proteínas Supressoras de Tumor/deficiência , Proteínas Supressoras de Tumor/genéticaRESUMO
Regulation of cell proliferation and motility is essential for normal development. The Rho family of GTPases plays a critical role in the control of cell polarity and migration by effecting the cytoskeleton, membrane trafficking, and cell adhesion. We investigated a recognized developmental disorder, Adams-Oliver syndrome (AOS), characterized by the combination of aplasia cutis congenita (ACC) and terminal transverse limb defects (TTLD). Through a genome-wide linkage analysis, we detected a locus for autosomal-dominant ACC-TTLD on 3q generating a maximum LOD score of 4.93 at marker rs1464311. Candidate-gene- and exome-based sequencing led to the identification of independent premature truncating mutations in the terminal exon of the Rho GTPase-activating protein 31 gene, ARHGAP31, which encodes a Cdc42/Rac1 regulatory protein. Mutant transcripts are stable and increase ARHGAP31 activity in vitro through a gain-of-function mechanism. Constitutively active ARHGAP31 mutations result in a loss of available active Cdc42 and consequently disrupt actin cytoskeletal structures. Arhgap31 expression in the mouse is substantially restricted to the terminal limb buds and craniofacial processes during early development; these locations closely mirror the sites of impaired organogenesis that characterize this syndrome. These data identify the requirement for regulated Cdc42 and/or Rac1 signaling processes during early human development.
Assuntos
Displasia Ectodérmica/genética , Proteínas Ativadoras de GTPase/genética , Mutação , Actinas/metabolismo , Adesão Celular , Movimento Celular , Polaridade Celular , Proliferação de Células , Mapeamento Cromossômico , Citoesqueleto/metabolismo , Análise Mutacional de DNA , Displasia Ectodérmica/embriologia , Feminino , Regulação da Expressão Gênica , Células HEK293 , Células HeLa , Humanos , Deformidades Congênitas dos Membros/embriologia , Deformidades Congênitas dos Membros/genética , Masculino , Dermatoses do Couro Cabeludo/congênito , Dermatoses do Couro Cabeludo/embriologia , Dermatoses do Couro Cabeludo/genética , Transdução de Sinais , Proteína cdc42 de Ligação ao GTP/metabolismo , Proteínas rac1 de Ligação ao GTP/metabolismoRESUMO
Sweat glands play a fundamental role in thermal regulation in man, but the molecular mechanism of their development remains unknown. To initiate analyses, we compared the model of Eda mutant Tabby mice, in which sweat glands were not formed, with wild-type (WT) mice. We inferred developmental stages and critical genes based on observations at seven time points spanning embryonic, postnatal and adult life. In WT footpads, sweat gland germs were detected at E17.5. The coiling of secretory portions started at postnatal day 1 (P1), and sweat gland formation was essentially completed by P5. Consistent with a controlled morphological progression, expression profiling revealed stage-specific gene expression changes. Similar to the development of hair follicles-the other major skin appendage controlled by EDA-sweat gland induction and initial progression were accompanied by Eda-dependent up-regulation of the Shh pathway. During the further development of sweat gland secretory portions, Foxa1 and Foxi1, not at all expressed in hair follicles, were progressively up-regulated in WT but not in Tabby footpads. Upon completion of WT development, Shh declined to Tabby levels, but Fox family genes remained at elevated levels in mature sweat glands. The results provide a framework for the further analysis of phased down-stream regulation of gene action, possibly by a signaling cascade, in response to Eda.
Assuntos
Displasia Ectodérmica/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Proteínas Hedgehog/metabolismo , Fator 3-alfa Nuclear de Hepatócito/metabolismo , Glândulas Sudoríparas/crescimento & desenvolvimento , Glândulas Sudoríparas/metabolismo , Animais , Displasia Ectodérmica/embriologia , Displasia Ectodérmica/genética , Feminino , Fatores de Transcrição Forkhead/genética , Regulação da Expressão Gênica no Desenvolvimento , Proteínas Hedgehog/genética , Fator 3-alfa Nuclear de Hepatócito/genética , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Família Multigênica , Glândulas Sudoríparas/embriologiaRESUMO
BACKGROUND: In this study, the mutated phenotypes were produced by treatment of chemical mutagen, N-ethyl-N-nitrosourea (ENU). We analyzed the mutated mice showing the specific phenotype of ectodermal dysplasia (ED) and examined the affected gene. METHODS: Phenotypes, including size, bone formation, and craniofacial morphology of ENU-induced ED mice, were focused. Tooth development and expression of several molecules were analyzed by histologic observations and immunohistochemistry. We carried out genome-wide screening and quantitative real-time PCR to define the affected and related genes. RESULTS: As examined previously in human ectodermal dysplasia, ENU-induced ED mice showed the specific morphologic deformities in tooth, hair, and craniofacial growth. Tooth development in the ENU-induced ED mice ceased at early cap stage. In addition, skeletal staining showed retardation in craniofacial development. Finally, the affected gene, which would be involved in the mechanism of ED, was located between the marker D3Mit14 and D3Mit319 on chromosome 3. CONCLUSIONS: The affected gene in ENU-induced ED mice showed several defects in ectodermal organogenesis and these results indicate that this gene plays an important role in mouse embryogenesis.
Assuntos
Displasia Ectodérmica/induzido quimicamente , Etilnitrosoureia/toxicidade , Anormalidades Dentárias/induzido quimicamente , Animais , Animais Recém-Nascidos , Mapeamento Cromossômico , Cromossomos de Mamíferos , Displasia Ectodérmica/embriologia , Displasia Ectodérmica/genética , Ectodisplasinas/genética , Ectodisplasinas/metabolismo , Feminino , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Subunidades beta de Inibinas/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Fator 1 de Ligação ao Facilitador Linfoide/genética , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Organogênese/efeitos dos fármacos , Transdução de Sinais/genética , Anormalidades Dentárias/embriologia , Anormalidades Dentárias/genética , Fator de Transcrição RelA/genéticaRESUMO
There has been progress in the application of stem cell transplantation for treatment of an increasing number of severe congenital and acquired bone marrow disorders, currently restricted by the availability of human leukocyte antigen (HLA)-matched related donors. Preimplantation HLA typing has recently been introduced to improve the access to stem cell therapy for inherited bone marrow failures. Preimplantation genetic diagnosis (PGD) provides an option not only for avoiding an affected pregnancy with thalassemia and other inherited disorders but also for preselection of the HLA-compatible donors for affected siblings. Multiple short tandem repeat markers throughout the HLA region are applied for this purpose, allowing 100% accuracy of HLA typing, through picking up possible recombination in the HLA region, as well as the copy number of chromosome 6, which affect accuracy of preimplantation HLA typing. Present experience of preimplantation HLA typing includes preimplantation HLA typing in 180 cycles, 122 of which were done as part of PGD for Fanconi anemia, thalassemia, Wiscott-Aldrich syndrome, hyper-immunoglobulin M syndrome, hypohidrotic ectodermal dysplasia with immune deficiency, and X-linked adrenoleukodystrophy, and 58 for the sole purpose of HLA typing for leukemias and for aplastic and Diamond-Blackfan anemia. The applied method resulted in the accurate preselection and transfer of 100% HLA-matched embryos, yielding already three dozen clinical pregnancies and the birth of two dozen HLA-matched children to the siblings requiring stem cell transplantation. Successful therapy with HLA-matched stem cells, obtained from these PGD children, has been achieved already for Diamond-Blackfan anemia hypohidrotic ectodermal dysplasia with immune deficiency and thalassemia.
Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical , Doenças Genéticas Inatas/genética , Engenharia Genética/métodos , Antígenos HLA/genética , Teste de Histocompatibilidade/métodos , Diagnóstico Pré-Implantação , Obtenção de Tecidos e Órgãos/métodos , Anemia de Diamond-Blackfan/diagnóstico , Anemia de Diamond-Blackfan/embriologia , Anemia de Diamond-Blackfan/prevenção & controle , Anemia de Diamond-Blackfan/cirurgia , Blastocisto , Bancos de Sangue , Displasia Ectodérmica/diagnóstico , Displasia Ectodérmica/embriologia , Displasia Ectodérmica/prevenção & controle , Displasia Ectodérmica/cirurgia , Transferência Embrionária , Fertilização in vitro , Doenças Fetais/diagnóstico , Doenças Genéticas Inatas/embriologia , Doenças Genéticas Inatas/prevenção & controle , Doenças Genéticas Inatas/cirurgia , Engenharia Genética/ética , Humanos , Diagnóstico Pré-Implantação/ética , Irmãos , Sequências de Repetição em Tandem , Talassemia/embriologia , Talassemia/genética , Talassemia/prevenção & controle , Talassemia/cirurgia , Obtenção de Tecidos e Órgãos/éticaRESUMO
In wild-type (WT) mice, epithelial apoptosis is involved in reducing the embryonic tooth number and the mesial delimitation of the first molar. We investigated whether apoptosis could also be involved in the reduction of tooth number and the determination of anomalous tooth boundaries in tabby (Ta)/EDA mice. Using serial histological sections and computer-aided 3D reconstructions, we investigated epithelial apoptosis in the lower cheek dentition at embryonic days 14.5-17.5. In comparison with WT mice, apoptosis was increased mainly mesially in Ta dental epithelium from day 15.5. This apoptosis showed a similar mesio-distal extent in all 5 morphotypes (Ia,b,c and IIa,b) of Ta dentition and eliminated the first cheek tooth in morphotypes IIa,b. Apoptosis did not appear to play any causal role in positioning inter-dental gaps. Analysis of the present data suggests that the increased apoptosis in Ta mice is a consequence of impaired tooth development caused by a defect in segmentation of dental epithelium.
Assuntos
Apoptose/fisiologia , Displasia Ectodérmica/embriologia , Morfogênese/fisiologia , Odontogênese/fisiologia , Germe de Dente/embriologia , Animais , Bochecha/embriologia , Displasia Ectodérmica/genética , Ectodisplasinas , Órgão do Esmalte/embriologia , Epitélio/embriologia , Idade Gestacional , Processamento de Imagem Assistida por Computador/métodos , Imageamento Tridimensional/métodos , Mandíbula/embriologia , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos , Camundongos MutantesRESUMO
OBJECTIVE: A supernumerary cheek tooth occurs mesially to the first molar in tabby/EDA (Ta) mice affected by hypohidrotic ectodermal dysplasia. The supernumerary tooth (S) has been hypothetically homologized to the premolar, which has disappeared during mouse evolution. DESIGN: This hypothesis was tested using available morphological data on the lower cheek teeth in wild type (WT) and Ta mice. RESULTS: The presence of S is accompanied by a reduction in the mesial portion of the M(1) in mutant mice. 3D reconstructions suggest that the S in Ta homo/hemizygous embryos originates from a split off the mesial portion of the first molar (M(1)) cap. In WT embryos, two vestigial tooth primordia are transiently distinct in front of the M(1). The distal vestige has the form of a wide bud and participates during the development of the mesial portion of the M(1). This bud has been homologized with the vestigial primordium of the fourth premolar of mouse ancestors. The premolar disappearance coincided with a mesial lengthening of the M(1) during mouse evolution. The incorporation of the distal premolar vestige into the mesial part of the M(1) in WT embryos can be regarded as a repetition of the premolar disappearance during evolution. CONCLUSION: : Ontogenetic and phylogenetic data support that the S in Ta mice arises due to the segregation of the distal premolar vestige from the molar dentition and thus represents an evolutionary throwback (atavism).
Assuntos
Dente Pré-Molar , Bochecha , Proteínas de Membrana/genética , Dente Supranumerário/patologia , Animais , Evolução Biológica , Displasia Ectodérmica/embriologia , Displasia Ectodérmica/patologia , Ectodisplasinas , Homozigoto , Camundongos , Camundongos Mutantes , Dente Supranumerário/embriologiaRESUMO
Ectodermal appendages such as skin, hair, teeth, and sweat glands are affected in patients with hypohidrotic (anhydrotic) ectodermal dysplasia (HED). It has been established that mutations in the tumor necrosis factor (TNF) superfamily of molecules, i.e., ectodysplasin (EDA), EDA receptor (EDAR), and EDAR-associated death domain (EDARADD; the intracellular adaptor for EDAR), are responsible for several forms of HED in humans and mice. We show here by in situ hybridisation that another TNF family (orphan) receptor, TROY (also known TAJ, TAJ-alpha, TRADE, and TNFRSF19), is strongly coexpressed with Edar in the epithelial enamel knot signalling centres that are believe to regulate cuspal morphogenesis during murine tooth development. Traf6 is known to function as an intracellular adaptor protein for Troy and examination of Traf6 mutant mice revealed abnormalities in molar teeth that are similar but more severe than those produced by mutations in Eda signalling molecules. This finding suggests that, in additional to ectodysplasin, another TNF pathway involving Troy/Traf6 is involved in molar tooth cusp formation and identifies an essential role for a Traf in tooth development. Developmental Dynamics 229:131-135, 2004.
Assuntos
Odontogênese/fisiologia , Proteínas/fisiologia , Animais , Sequência de Bases , DNA Complementar/genética , Esmalte Dentário/embriologia , Displasia Ectodérmica/embriologia , Displasia Ectodérmica/genética , Ectodisplasinas , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Proteínas de Membrana/genética , Proteínas de Membrana/fisiologia , Camundongos , Camundongos Mutantes , Dente Molar/anormalidades , Dente Molar/embriologia , Mutação , Odontogênese/genética , Fenótipo , Proteínas/genética , Receptores do Fator de Necrose Tumoral/genética , Receptores do Fator de Necrose Tumoral/fisiologia , Fator 6 Associado a Receptor de TNFRESUMO
OBJECTIVES: Prenatal identification of the different dentition morphotypes, which exist in the lower molar region of tabby (Ta) adult mice, and investigation of their origin. The mouse Ta syndrome and its counterpart anhidrotic (hypohidrotic) ectodermal dysplasia (EDA) in human are characterized by absence or hypoplasia of sweat glands, hair and teeth. DESIGN: Analysis of tooth morphogenesis using serial histological sections and 3D computer aided reconstructions of the dental epithelium in the cheek region of the mandible. SETTING AND SAMPLE POPULATION: Institute of Experimental Medicine, Academy of Sciences, Prague. Heads of 75 Ta homozygous and hemizygous mice and 40 wild type (WT) control mice aged from embryonic day (ED) 14.0-20.5 (newborns), harvested during 1995-2001. OUTCOME MEASURE: Prenatal identification of five distinct morphotypes of Ta dentition on the basis of differences in tooth number, size, shape, position and developmental stage and of the morphology of the enamel knot in the most mesial tooth primordium. RESULTS: The mesio-distal length of the dental epithelium was similar in the lower cheek region in Ta and WT mice. In Ta embryos, there was altered the mesio-distal segmentation of the dental epithelium giving rise to the individual tooth primordia. Prenatally, two basic morphotypes I and II and their particular subtypes (Ia, Ib, Ic, and IIa, IIb, respectively) of the developing dentition were identified from day 15.5. The incidence of the distinct morphotypes in the present sample did not differ from postnatal data. The proportion of the morphotype I and II was dependent on mother genotype. CONCLUSION: The different dentition morphotypes in Ta mice originate from a defect in the mesio-distal segmentation of the dental epithelium in mouse embryos. This defect presumably leads to variable positions of tooth boundaries that do not correspond to those of the WT molars. One tooth primordium of Ta mice might be derived from adjacent parts of two molar primordia in WT mice.
Assuntos
Displasia Ectodérmica/patologia , Dente Molar/anormalidades , Anormalidades Dentárias/embriologia , Germe de Dente/anormalidades , Animais , Modelos Animais de Doenças , Displasia Ectodérmica/embriologia , Displasia Ectodérmica/genética , Epitélio/embriologia , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/embriologia , Humanos , Hipo-Hidrose/embriologia , Hipo-Hidrose/genética , Hipo-Hidrose/patologia , Processamento de Imagem Assistida por Computador , Masculino , Mandíbula , Camundongos , Camundongos Mutantes , Dente Molar/embriologia , Morfogênese , Odontogênese , Odontometria , Germe de Dente/embriologiaRESUMO
OBJECTIVE: Hypohidrotic ectodermal dysplasia (HED) comprises defects in hair, teeth, and sweat glands. Disturbances in other ectodermal tissues have been associated with the condition. Our objective was to examine ectodermal craniofacial structures histologically in a fetus with HED and to compare the findings to similar structures in normal control fetuses. MATERIALS AND METHODS: A male fetus diagnosed with HED was therapeutically aborted in the 15th week of gestation. One male and two female healthy fetuses were used as normal controls. All fetuses were examined with parental consent, and had comparable sizes. Their bone maturation stage in the hand was identical. Tissue blocks from the craniofacial region were excised from all fetuses and prepared for histological analysis (formalin fixed, stained with toluidine blue or Alcian blue). The tissues examined were: tooth buds, skin and skin appendages, oral mucosa including minor salivary glands, major salivary glands, lacrimal glands, and adenohypophysis. RESULTS: Fewer tooth buds, minor salivary glands, and hair follicles were observed in the HED fetus as compared to controls. The structures of the epidermal components in the developing HED organs were loose and disorganised. The adhesion between the ectodermal and mesenchymal organ components in the HED fetus seemed to be disturbed.
Assuntos
Displasia Ectodérmica/embriologia , Displasia Ectodérmica/patologia , Desenvolvimento Embrionário e Fetal , Feminino , Feto/patologia , Humanos , Recém-Nascido , Aparelho Lacrimal/embriologia , Aparelho Lacrimal/patologia , Masculino , Mucosa Bucal/embriologia , Mucosa Bucal/patologia , Adeno-Hipófise/embriologia , Adeno-Hipófise/patologia , Glândulas Salivares/embriologia , Glândulas Salivares/patologia , Pele/embriologia , Pele/patologia , Germe de Dente/embriologia , Germe de Dente/patologiaAssuntos
Anormalidades Craniofaciais/genética , Fissura Palatina/embriologia , Fissura Palatina/genética , Anormalidades Craniofaciais/embriologia , Craniossinostoses/embriologia , Displasia Ectodérmica/embriologia , Displasia Ectodérmica/genética , Desenvolvimento Embrionário e Fetal/genética , Feminino , Humanos , GravidezRESUMO
We report on a newborn black male twin with a distinctive circumferential abdominal skin defect who was identified through the Active Malformation Surveillance Program at the Brigham and Women's Hospital. There were no other malformations, and amniotic disruption was not present. Although it cannot be proven, we believe that this skin defect may have been caused by in utero encirclement of the abdomen by an umbilical cord.