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The tbx/bHLH transcription factor mga regulates gata4 and organogenesis.

ABSTRACT: The mga gene encodes a unique transcription factor containing both TBOX and bHLHzip DNA-binding domains. Here we describe the structure, expression pattern, and loss-of-function phenotype for zebrafish mga. The mga gene is conserved with mammalian homologs for both DNA-binding domains. It is expressed maternally, and subsequently in the developing brain, heart, and gut, and its depletion causes morphogenetic defects in each of these organ systems. The heart and gut phenotypes are similar to those described previously for loss of gata4, and the mga morphant shows increased levels of gata4 transcripts in lateral mesoderm. Knockdown of gata4 rescues the early heart-looping defect (but not the gut defect), indicating that mga restricts the normal levels of Gata4 required for heart tube looping, while both genes are important for gut development. Transcript profiling experiments show that mga functions early to influence key regulators of mesendoderm, including tbx6, cas, and sox17.

SUBMITTER: Rikin A

PROVIDER: S-EPMC3613857 | biostudies-literature | 2010 Feb

REPOSITORIES: biostudies-literature

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The tbx/bHLH transcription factor mga regulates gata4 and organogenesis.

Rikin Amir A Evans Todd T

Developmental dynamics : an official publication of the American Association of Anatomists 20100201 2

The mga gene encodes a unique transcription factor containing both TBOX and bHLHzip DNA-binding domains. Here we describe the structure, expression pattern, and loss-of-function phenotype for zebrafish mga. The mga gene is conserved with mammalian homologs for both DNA-binding domains. It is expressed maternally, and subsequently in the developing brain, heart, and gut, and its depletion causes morphogenetic defects in each of these organ systems. The heart and gut phenotypes are similar to thos ...[more]

PMID: 20044811

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Project description:HLTF/Hltf regulates transcription, remodels chromatin, and coordinates DNA damage repair. Hltf is expressed in mouse brain and heart during embryonic and postnatal development. Silencing Hltf is semilethal. Seventy-four percent of congenic C57BL/6J Hltf knockout mice died, 75% within 12-24 hours of birth. Previous studies in neonatal (6-8 hour postpartum) brain revealed silencing Hltf disrupted cell cycle progression, and attenuated DNA damage repair. An RNA-Seq snapshot of neonatal heart transcriptome showed 1,536 of 20,000 total transcripts were altered (p < 0.05) - 10 up- and 1,526 downregulated. Pathway enrichment analysis with MetaCore™ showed Hltf's regulation of the G2/M transition (p=9.726E(-15)) of the cell cycle in heart is nearly identical to its role in brain. In addition, Brca1 and 12 members of the Brca1 associated genome surveillance complex are also downregulated. Activation of caspase 3 coincides with transcriptional repression of Bcl-2. Hltf loss caused downregulation of Wt1/Gata4/Hif-1a signaling cascades as well as Myh7b/miR499 transcription. Hltf-specific binding to promoters and/or regulatory regions of these genes was authenticated by ChIP-PCR. Hif-1a targets for prolyl (P4ha1, P4ha2) and lysyl (Plod2) collagen hydroxylation, PPIase enzymes (Ppid, Ppif, Ppil3) for collagen trimerization, and lysyl oxidase (Loxl2) for collagen-elastin crosslinking were downregulated. However, transcription of genes for collagens, fibronectin, Mmps and their inhibitors (Timps) was unaffected. The collective downregulation of genes whose protein products control collagen biogenesis caused disorganization of the interstitial and perivascular myocardial collagen fibrillar network as viewed with picrosirius red-staining, and authenticated with spectral imaging. Wavy collagen bundles in control hearts contrasted with collagen fibers that were thin, short and disorganized in Hltf null hearts. Collagen bundles in Hltf null hearts were tangled and fragmented. Thus, silencing Hltf during heart organogenesis compromised DNA double-strand break repair, and caused aberrant collagen biogenesis altering the structural network that transmits cardiomyocyte force into muscle contraction.

Dataset Information

The tbx/bHLH transcription factor mga regulates gata4 and organogenesis.

Publications

The tbx/bHLH transcription factor mga regulates gata4 and organogenesis.

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