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A Myc-Groucho complex integrates EGF and Notch signaling to regulate neural development.

ABSTRACT: Integration of patterning cues via transcriptional networks to coordinate gene expression is critical during morphogenesis and misregulated in cancer. Using DNA adenine methyltransferase (Dam)ID chromatin profiling, we identified a protein-protein interaction between the Drosophila Myc oncogene and the Groucho corepressor that regulates a subset of direct dMyc targets. Most of these shared targets affect fate or mitosis particularly during neurogenesis, suggesting the dMyc-Groucho complex may coordinate fate acquisition with mitotic capacity during development. We find an antagonistic relationship between dMyc and Groucho that mimics the antagonistic interactions found for EGF and Notch signaling: dMyc is required to specify neuronal fate and enhance neuroblast mitosis, whereas Groucho is required to maintain epithelial fate and inhibit mitosis. Our results suggest that the dMyc-Groucho complex defines a previously undescribed mechanism of Myc function and may serve as the transcriptional unit that integrates EGF and Notch inputs to regulate early neuronal development.

SUBMITTER: Orian A

PROVIDER: S-EPMC2000393 | biostudies-literature | 2007 Oct

REPOSITORIES: biostudies-literature

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A Myc-Groucho complex integrates EGF and Notch signaling to regulate neural development.

Orian Amir A Delrow Jeffrey J JJ Rosales Nieves Alicia E AE Abed Mona M Metzger David D Paroush Ze'ev Z Eisenman Robert N RN Parkhurst Susan M SM

Proceedings of the National Academy of Sciences of the United States of America 20070926 40

Integration of patterning cues via transcriptional networks to coordinate gene expression is critical during morphogenesis and misregulated in cancer. Using DNA adenine methyltransferase (Dam)ID chromatin profiling, we identified a protein-protein interaction between the Drosophila Myc oncogene and the Groucho corepressor that regulates a subset of direct dMyc targets. Most of these shared targets affect fate or mitosis particularly during neurogenesis, suggesting the dMyc-Groucho complex may co ...[more]

PMID: 17898168

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Project description:BACKGROUND:Cellular differentiation is a critical process during development of multicellular animals that must be tightly controlled in order to avoid precocious differentiation or failed generation of differentiated cell types. Research in flies, vertebrates, and nematodes has led to the identification of a conserved role for Notch signaling as a mechanism to regulate cellular differentiation regardless of tissue/cell type. Notch signaling can occur through a canonical pathway that results in the activation of hes gene expression by a complex consisting of the Notch intracellular domain, SuH, and the Mastermind co-activator. Alternatively, Notch signaling can occur via a non-canonical mechanism that does not require SuH or activation of hes gene expression. Regardless of which mechanism is being used, high Notch activity generally inhibits further differentiation, while low Notch activity promotes differentiation. Flies, vertebrates, and nematodes are all bilaterians, and it is therefore unclear if Notch regulation of differentiation is a bilaterian innovation, or if it represents a more ancient mechanism in animals. RESULTS:To reconstruct the ancestral function of Notch signaling we investigate Notch function in a non-bilaterian animal, the sea anemone Nematostella vectensis (Cnidaria). Morpholino or pharmacological knockdown of Nvnotch causes increased expression of the neural differentiation gene NvashA. Conversely, overactivation of Notch activity resulting from overexpression of the Nvnotch intracellular domain or by overexpression of the Notch ligand Nvdelta suppresses NvashA. We also knocked down or overactivated components of the canonical Notch signaling pathway. We disrupted NvsuH with morpholino or by overexpressing a dominant negative NvsuH construct. We saw no change in expression levels for Nvhes genes or NvashA. Overexpression of Nvhes genes did not alter NvashA expression levels. Lastly, we tested additional markers associated with neuronal differentiation and observed that non-canonical Notch signaling broadly suppresses neural differentiation in Nematostella. CONCLUSIONS:We conclude that one ancestral role for Notch in metazoans was to regulate neural differentiation. Remarkably, we found no evidence for a functional canonical Notch pathway during Nematostella embryogenesis, suggesting that the non-canonical hes-independent Notch signaling mechanism may represent an ancestral Notch signaling pathway.

Project description:In response to environmental light signals, transcriptomic adjustment plays an important role in Arabidopsis seed germination and seedling development. G-box cis-element is commonly present in promoters of genes positively or negatively responding to the light signal. For the pursuit of additional transcriptional regulator modulating light-mediated transcriptome changes, we have identified AtbZIP16, a basic region/leucine zipper motif transcription factor, via G-box DNA affinity chromatography. We have confirmed that AtbZIP16 possesses G-box-specific binding activity. Analyses of atbzip16 mutants indicate that AtbZIP16 is a negative regulator in phyB-mediated inhibition of cell elongation, but a positive regulator in phytochrome-mediated seed germination process. Transcriptomic analysis supports that AtbZIP16 is primarily a transcriptional repressor regulating light-, GA- and ABA-responsive genes. Chromatin immunoprecipitation study revealed that AtbZIP16 could directly target RGL2, a DELLA gene, and indirectly repress the expression of PIL5 gene, which encodes a bHLH protein inhibiting seed germination in Arabidopsis. Our study indicated that, through repressing the expression of RGL2 and the antagonizing the expression of PIL5, AtbZIP16 functions to promote seed germination and hypocotyl elongation during early stages of Arabidopsis seedling development. In response to environmental light signals, transcriptomic adjustment plays an important role in Arabidopsis seed germination and seedling development. G-box cis-element is commonly present in promoters of genes positively or negatively responding to the light signal. For the pursuit of additional transcriptional regulator modulating light-mediated transcriptome changes, we have identified AtbZIP16, a basic region/leucine zipper motif transcription factor, via G-box DNA affinity chromatography. We have confirmed that AtbZIP16 possesses G-box-specific binding activity. Analyses of atbzip16 mutants indicate that AtbZIP16 is a negative regulator in phyB-mediated inhibition of cell elongation, but a positive regulator in phytochrome-mediated seed germination process. Transcriptomic analysis supports that AtbZIP16 is primarily a transcriptional repressor regulating light-, GA- and ABA-responsive genes. Chromatin immunoprecipitation study revealed that AtbZIP16 could directly target RGL2, a DELLA gene, and indirectly repress the expression of PIL5 gene, which encodes a bHLH protein inhibiting seed germination in Arabidopsis. Our study indicated that, through repressing the expression of RGL2 and the antagonizing the expression of PIL5, AtbZIP16 functions to promote seed germination and hypocotyl elongation during early stages of Arabidopsis seedling development. Three biological replicates for 4-d-old seedlings grown under dark or red-light and long-day (0.5 ?mole m-2 sec-1) contitions.

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A Myc-Groucho complex integrates EGF and Notch signaling to regulate neural development.

Publications

A Myc-Groucho complex integrates EGF and Notch signaling to regulate neural development.

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