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Modulation of morphogenesis by noncanonical Wnt signaling requires ATF/CREB family-mediated transcriptional activation of TGFbeta2.

ABSTRACT: Transcriptional readout downstream of canonical Wnt signaling is known to be mediated by beta-catenin activation of well-described targets, but potential transcriptional readout in response to noncanonical Wnt signaling remains poorly understood. Here, we define a transcriptional pathway important in noncanonical Wnt signaling. We have found that Wnt11 is a direct target of a canonical beta-catenin pathway in developing heart and that Wnt11 mutants show cardiac outflow tract defects. We provide genetic and biochemical evidence thatWnt11 signaling affects extracellular matrix composition, cytoskeletal rearrangements and polarized cell movement required for morphogenesis of the cardiac outflow tract. Notably, transforming growth factor beta2 (TGFbeta2), a key effector of organ morphogenesis, is regulated by Wnt11-mediated noncanonical signaling in developing heart and somites via one or more activating transcription factor (ATF)/cyclic AMP response element binding protein (CREB) family members. Thus, we propose that transcriptional readout mediated at least in part by a Wnt11 --> ATF/CREB --> TGFbeta2 pathway is critical in regulating morphogenesis in response to noncanonical Wnt signaling.

SUBMITTER: Zhou W

PROVIDER: S-EPMC5578467 | biostudies-literature | 2007 Oct

REPOSITORIES: biostudies-literature

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Modulation of morphogenesis by noncanonical Wnt signaling requires ATF/CREB family-mediated transcriptional activation of TGFbeta2.

Zhou Wenlai W Lin Lizhu L Majumdar Arindam A Li Xue X Zhang Xiaoxue X Liu Wei W Etheridge Leah L Shi Yunqing Y Martin James J Van de Ven Wim W Kaartinen Vesa V Wynshaw-Boris Anthony A McMahon Andrew P AP Rosenfeld Michael G MG Evans Sylvia M SM

Nature genetics 20070902 10

Transcriptional readout downstream of canonical Wnt signaling is known to be mediated by beta-catenin activation of well-described targets, but potential transcriptional readout in response to noncanonical Wnt signaling remains poorly understood. Here, we define a transcriptional pathway important in noncanonical Wnt signaling. We have found that Wnt11 is a direct target of a canonical beta-catenin pathway in developing heart and that Wnt11 mutants show cardiac outflow tract defects. We provide ...[more]

PMID: 17767158

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Project description:ObjectiveLoss of insulin secretion due to failure or death of the insulin secreting ? cells is the central cause of diabetes. The cellular response to stress (endoplasmic reticulum (ER), oxidative, inflammatory) is essential to sustain normal ? cell function and survival. Pancreatic and duodenal homeobox 1 (PDX1), Activating transcription factor 4 (ATF4), and Activating transcription factor 5 (ATF5) are transcription factors implicated in ? cell survival and susceptibility to stress. Our goal was to determine if a PDX1-ATF transcriptional complex or complexes regulate ? cell survival in response to stress and to identify direct transcriptional targets.MethodsPdx1, Atf4 and Atf5 were silenced by viral delivery of gRNAs or shRNAs to Min6 insulinoma cells or primary murine islets. Gene expression was assessed by qPCR, RNAseq analysis, and Western blot analysis. Chromatin enrichment was measured in the Min6 ? cell line and primary isolated mouse islets by ChIPseq and ChIP PCR. Immunoprecipitation was used to assess interactions among transcription factors in Min6 cells and isolated mouse islets. Activation of caspase 3 by immunoblotting or by irreversible binding to a fluorescent inhibitor was taken as an indication of commitment to an apoptotic fate.ResultsRNASeq identified a set of PDX1, ATF4 and ATF5 co-regulated genes enriched in stress and apoptosis functions. We further identified stress induced interactions among PDX1, ATF4, and ATF5. PDX1 chromatin occupancy peaks were identified over composite C/EBP-ATF (CARE) motifs of 26 genes; assessment of a subset of these genes revealed co-enrichment for ATF4 and ATF5. PDX1 occupancy over CARE motifs was conserved in the human orthologs of 9 of these genes. Of these, Glutamate Pyruvate Transaminase 2 (Gpt2), Cation transport regulator 1 (Chac1), and Solute Carrier Family 7 Member 1 (Slc7a1) induction by stress was conserved in human islets and abrogated by deficiency of Pdx1, Atf4, and Atf5 in Min6 cells. Deficiency of Gpt2 reduced ? cell susceptibility to stress induced apoptosis in both Min6 cells and primary islets.ConclusionsOur results identify a novel PDX1 stress inducible complex (es) that regulates expression of stress and apoptosis genes to govern ? cell survival.

Dataset Information

Modulation of morphogenesis by noncanonical Wnt signaling requires ATF/CREB family-mediated transcriptional activation of TGFbeta2.

Publications

Modulation of morphogenesis by noncanonical Wnt signaling requires ATF/CREB family-mediated transcriptional activation of TGFbeta2.

Similar Datasets

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