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Cell Rep ; 14(4): 850-860, 2016 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-26776518


Feeding is an evolutionarily conserved and integral behavior that depends on the rhythmic activity of feeding muscles stimulated by specific motoneurons. However, critical molecular determinants underlying the development of the neuromuscular feeding unit are largely unknown. Here, we identify the Hox transcription factor Deformed (Dfd) as essential for feeding unit formation, from initial specification to the establishment of active synapses, by controlling stage-specific sets of target genes. Importantly, we found Dfd to control the expression of functional components of synapses, such as Ankyrin2-XL, a protein known to be critical for synaptic stability and connectivity. Furthermore, we uncovered Dfd as a potential regulator of synaptic specificity, as it represses expression of the synaptic cell adhesion molecule Connectin (Con). These results demonstrate that Dfd is critical for the establishment and maintenance of the neuromuscular unit required for feeding behavior, which might be shared by other group 4 Hox genes.

Proteínas de Drosophila/metabolismo , Proteínas de Homeodomínio/metabolismo , Neurônios Motores/metabolismo , Junção Neuromuscular/metabolismo , Animais , Anquirinas/metabolismo , Conectina/metabolismo , Drosophila , Proteínas de Drosophila/genética , Comportamento Alimentar , Proteínas de Homeodomínio/genética , Neurônios Motores/citologia , Neurogênese , Junção Neuromuscular/crescimento & desenvolvimento
EMBO J ; 31(15): 3323-33, 2012 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-22781127


Precise gene expression is a fundamental aspect of organismal function and depends on the combinatorial interplay of transcription factors (TFs) with cis-regulatory DNA elements. While much is known about TF function in general, our understanding of their cell type-specific activities is still poor. To address how widely expressed transcriptional regulators modulate downstream gene activity with high cellular specificity, we have identified binding regions for the Hox TF Deformed (Dfd) in the Drosophila genome. Our analysis of architectural features within Hox cis-regulatory response elements (HREs) shows that HRE structure is essential for cell type-specific gene expression. We also find that Dfd and Ultrabithorax (Ubx), another Hox TF specifying different morphological traits, interact with non-overlapping regions in vivo, despite their similar DNA binding preferences. While Dfd and Ubx HREs exhibit comparable design principles, their motif compositions and motif-pair associations are distinct, explaining the highly selective interaction of these Hox proteins with the regulatory environment. Thus, our results uncover the regulatory code imprinted in Hox enhancers and elucidate the mechanisms underlying functional specificity of TFs in vivo.

Drosophila/genética , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/fisiologia , Elementos de Resposta/genética , Fatores de Transcrição/metabolismo , Animais , Animais Geneticamente Modificados , Sítios de Ligação/genética , Drosophila/embriologia , Proteínas de Drosophila/metabolismo , Proteínas de Drosophila/fisiologia , Embrião não Mamífero , Regulação da Expressão Gênica no Desenvolvimento , Genes Homeobox , Genes de Insetos , Código das Histonas/genética , Código das Histonas/fisiologia , Proteínas de Homeodomínio/metabolismo , Modelos Biológicos , Ligação Proteica , Fatores de Transcrição/fisiologia , Ativação Transcricional
PLoS Genet ; 8(3): e1002582, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22438831


Apoptosis is essential to prevent oncogenic transformation by triggering self-destruction of harmful cells, including those unable to differentiate. However, the mechanisms linking impaired cell differentiation and apoptosis during development and disease are not well understood. Here we report that the Drosophila transcription factor Cut coordinately controls differentiation and repression of apoptosis via direct regulation of the pro-apoptotic gene reaper. We also demonstrate that this regulatory circuit acts in diverse cell lineages to remove uncommitted precursor cells in status nascendi and thereby interferes with their potential to develop into cancer cells. Consistent with the role of Cut homologues in controlling cell death in vertebrates, we find repression of apoptosis regulators by Cux1 in human cancer cells. Finally, we present evidence that suggests that other lineage-restricted specification factors employ a similar mechanism to put the brakes on the oncogenic process.

Apoptose , Diferenciação Celular , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Proteínas de Homeodomínio/genética , Proteínas Nucleares/genética , Fatores de Transcrição/genética , Animais , Apoptose/genética , Diferenciação Celular/genética , Linhagem da Célula , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Modelos Animais de Doenças , Proteínas de Drosophila/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Genes Supressores de Tumor , Células HEK293 , Proteínas de Homeodomínio/metabolismo , Humanos , Proteínas Nucleares/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Fatores de Transcrição/metabolismo