RESUMO
The mammalian dentition is a serially homogeneous structure that exhibits wide numerical and morphological variation among multiple different species. Patterning of the dentition is achieved through complex reiterative molecular signaling interactions that occur throughout the process of odontogenesis. The secreted signaling molecule Sonic hedgehog (Shh) plays a key role in this process, and the Shh coreceptor growth arrest-specific 1 (Gas1) is expressed in odontogenic mesenchyme and epithelium during multiple stages of tooth development. We show that mice engineered with Gas1 loss-of-function mutation have variation in number, morphology, and size of teeth within their molar dentition. Specifically, supernumerary teeth with variable morphology are present mesial to the first molar with high penetrance, while molar teeth are characterized by the presence of both additional and absent cusps, combined with reduced dimensions and exacerbated by the presence of a supernumerary tooth. We demonstrate that the supernumerary tooth in Gas1 mutant mice arises through proliferation and survival of vestigial tooth germs and that Gas1 function in cranial neural crest cells is essential for the regulation of tooth number, acting to restrict Wnt and downstream FGF signaling in odontogenic epithelium through facilitation of Shh signal transduction. Moreover, regulation of tooth number is independent of the additional Hedgehog coreceptors Cdon and Boc, which are also expressed in multiple regions of the developing tooth germ. Interestingly, further reduction of Hedgehog pathway activity in Shhtm6Amc hypomorphic mice leads to fusion of the molar field and reduced prevalence of supernumerary teeth in a Gas1 mutant background. Finally, we demonstrate defective coronal morphology and reduced coronal dimensions in the molar dentition of human subjects identified with pathogenic mutations in GAS1 and SHH/GAS1, suggesting that regulation of Hedgehog signaling through GAS1 is also essential for normal patterning of the human dentition.
Assuntos
Proteínas Hedgehog , Dente Supranumerário , Animais , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Dentição , Proteínas Ligadas por GPI , Regulação da Expressão Gênica no Desenvolvimento , Proteínas Hedgehog/metabolismo , Humanos , Mamíferos/genética , Mamíferos/metabolismo , Camundongos , Odontogênese , Transdução de Sinais/fisiologia , Dente Supranumerário/genéticaRESUMO
Cleft lip with or without palate (CLP) and isolated cleft palate (CP) are common human developmental malformations with a complex etiology that reflects a failure of normal facial development. VAX1 encodes a homeobox-containing transcription factor identified as a candidate gene for CLP in human populations, with targeted deletion in mice associated with multiple anomalies, including disruption of the visual apparatus and basal forebrain, lobar holoprosencephaly, and CP. We have investigated Vax1 function during murine palatogenesis but found no evidence for a direct role in this process. Vax1 is not expressed in the developing palate and mutant palatal shelves elevate above the tongue, demonstrating morphology and proliferation indices indistinguishable from wild type. However, mutant mice did have a large midline cavity originating from the embryonic forebrain situated beneath the floor of the hypothalamus and extending through the nasal cavity to expand this region and prevent approximation of the palatal shelves. Interestingly, despite strong expression of Vax1 in ectoderm of the medial nasal processes, the upper lip remained intact in mutant mice. We found further evidence of disrupted craniofacial morphology in Vax1 mutants, including truncation of the midface associated with reduced cell proliferation in forebrain neuroectoderm and frontonasal mesenchyme. Sonic hedgehog (Shh) signal transduction was downregulated in the mutant forebrain, consistent with a role for Vax1 in mediating transduction of this pathway. However, Shh was also reduced in this region, suggestive of a Shh-Vax1 feedback loop during early development of the forebrain and a likely mechanism for the underlying lobar holoprosencephaly. Despite significant associations between VAX1 and human forms of CLP, we find no evidence of a direct role for this transcription factor in development of this region in a mutant mouse model.
Assuntos
Fissura Palatina/genética , Proteínas de Homeodomínio/genética , Neuropeptídeos/genética , Animais , Proliferação de Células , Modelos Animais de Doenças , Regulação da Expressão Gênica no Desenvolvimento , Holoprosencefalia/genética , Camundongos , Fenótipo , Prosencéfalo/anormalidades , Transdução de Sinais , Fatores de Transcrição/genéticaRESUMO
Supernumerary teeth are a common clinical and radiographic finding and may produce occlusal and dental problems. The aetiological basis of extra teeth is poorly understood in human populations; however, the mouse provides a useful model system to investigate the complex genetics of tooth development. This article describes recent advances in our understanding of the genetic basis of supernumerary teeth. We have reviewed biological evidence that provides insight into why supernumerary tooth formation may occur. Indeed, many of the molecular signalling pathways known to be involved in normal development of the tooth germ can also give rise to additional teeth if inappropriately regulated. These include components of the Hedgehog, FGF, Wnt, TNF and BMP families, which provide a useful resource of candidate genes that may potentially play a role in human supernumerary tooth formation.
Assuntos
Dente Supranumerário/genética , Animais , Modelos Animais de Doenças , Fatores de Crescimento de Fibroblastos/genética , Proteínas Hedgehog/genética , Humanos , Camundongos , Epidemiologia Molecular , Odontogênese/genética , Transdução de Sinais/genética , Dente Supranumerário/epidemiologia , Fatores de Necrose Tumoral/genética , Proteínas Wnt/genéticaRESUMO
BACKGROUND: Treatment of latent tuberculosis (TB) infection (LTBI) in Brazil is recommended only in the case of contacts of pulmonary smear-positive TB patients aged
Assuntos
Portador Sadio/epidemiologia , Transmissão de Doença Infecciosa/estatística & dados numéricos , Tuberculose Pulmonar/epidemiologia , Tuberculose Pulmonar/transmissão , Adolescente , Adulto , Antituberculosos/uso terapêutico , Brasil , Portador Sadio/diagnóstico , Estudos de Coortes , Transmissão de Doença Infecciosa/prevenção & controle , Feminino , Humanos , Incidência , Isoniazida/uso terapêutico , Masculino , Pessoa de Meia-Idade , Guias de Prática Clínica como Assunto , Valor Preditivo dos Testes , Pirazinamida/uso terapêutico , Estudos Retrospectivos , Rifampina/uso terapêutico , Risco , Teste Tuberculínico , Tuberculose Pulmonar/diagnóstico , Tuberculose Pulmonar/tratamento farmacológico , Adulto JovemRESUMO
AIM: To investigate in individuals with symptomatic dental abscesses the occurrence of functional polymorphisms within five genes involved with the immune response. The functional gene polymorphisms analysed were CD14 (-260 C/T), IL1B (+3954 C/T), IL6 (-174 G/C,), IL10 (-1082 G/A) and TNFA (-308 G/A). METHODOLOGY: Genomic DNA obtained from oral swabs from individuals with symptomatic dental abscesses and asymptomatic inflammatory periapical lesions, without previous exacerbation, was submitted to restriction fragment length polymorphism (RFLP) analyses to determine each individual genotype. The chi-square and principal components analysis tests were used for statistical analysis. RESULTS: A significant association was observed between the occurrence of the GG genotype or the G allele expression of the polymorphic locus-174 (G/C) of the IL6 gene, and the presence of the symptomatic dental abscesses in women and in individuals < or =35 years old. The principal components analysis suggested predominance of the symptomatic dental abscesses in individuals displaying: high-producer IL6 genotype; intermediate and high-producer IL1B genotypes and low-producer TNFA genotype. CONCLUSIONS: The present study suggests that genetic factors are associated with susceptibility to develop symptomatic dental abscesses.