Transmembrane protein 88: a Wnt regulatory protein that specifies cardiomyocyte development

Palpant, Nathan J.; Pabon, Lil; Rabinowitz, Jeremy S.; Hadland, Brandon; Stoick-Cooper, Cristi L.; Paige, Sharon L.; Bernstein, Irwin D.; Moon, Randall T.; Murry, Charles E.

doi:10.1242/dev.094789

Cited by 58 publications

(80 citation statements)

References 41 publications

(62 reference statements)

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“…tmem88a knockdown enhanced this gradient, suggesting that the relationship between tmem88a and wnt11, potentially mediated by the known interaction between tmem88a and dvl (Lee et al, 2010), appears more complex than a simple activation or inactivation. Notably, two additional studies have been published during the review of our manuscript (Novikov and Evans, 2013;Palpant et al, 2013), both confirming a Wnt-dependent role for tmem88a in cardiomyocyte differentiation. The number of vertebrate phenotypes potentially observable even within the finite timeframe of embryonic development is vast.…”

Section: Research Articlesupporting

confidence: 55%

Novel cardiovascular gene functions revealed via systematic phenotype prediction in zebrafish

et al. 2014

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Comprehensive functional annotation of vertebrate genomes is fundamental to biological discovery. Reverse genetic screening has been highly useful for determination of gene function, but is untenable as a systematic approach in vertebrate model organisms given the number of surveyable genes and observable phenotypes. Unbiased prediction of gene-phenotype relationships offers a strategy to direct finite experimental resources towards likely phenotypes, thus maximizing de novo discovery of gene functions. Here we prioritized genes for phenotypic assay in zebrafish through machine learning, predicting the effect of loss of function of each of 15,106 zebrafish genes on 338 distinct embryonic anatomical processes. Focusing on cardiovascular phenotypes, the learning procedure predicted known knockdown and mutant phenotypes with high precision. In proof-ofconcept studies we validated 16 high-confidence cardiac predictions using targeted morpholino knockdown and initial blinded phenotyping in embryonic zebrafish, confirming a significant enrichment for cardiac phenotypes as compared with morpholino controls. Subsequent detailed analyses of cardiac function confirmed these results, identifying novel physiological defects for 11 tested genes. Among these we identified tmem88a, a recently described attenuator of Wnt signaling, as a discrete regulator of the patterning of intercellular coupling in the zebrafish cardiac epithelium. Thus, we show that systematic prioritization in zebrafish can accelerate the pace of developmental gene function discovery. KEY WORDS: Systems biology, Zebrafish, Cardiovascular, tmem88a INTRODUCTIONDe novo gene function discovery has been greatly facilitated by systematic gene deletion and observation of resulting phenotypes in scalable model organisms. Indeed, systematic gene disruptions in S. cerevisiae (Costanzo et al., 2010; Giaever et al., 2002), C. elegans (Kamath et al., 2003) and Drosophila (Boutros et al., 2004) have each revealed molecular functions for thousands of genes. However, given the breadth and complexity of observable phenotypes in vertebrates, comprehensive assessment of gene function through serial observation of all possible phenotypes following gene disruption remains infeasible. A more efficient alternative would be to use gene function prediction to prioritize gene candidates for more detailed phenotypic testing based on a variety of known gene and protein properties and relationships. RESEARCH ARTICLE TECHNIQUES AND RESOURCESComputational prediction of molecular function has been effective in assigning physiological roles to genes across eukaryotic model organisms (Deng et al., 2004;Guan et al., 2008; Huttenhower et al., 2009;Karaoz et al., 2004;Lee et al., 2004;Mostafavi et al., 2008;Tasan et al., 2012;Tasan et al., 2008;Troyanskaya et al., 2003). Similar prediction frameworks have been applied to predict associated phenotypes in yeast (King et al., 2003;Saha and Heber, 2006) and worm and to identify putative human disease gene candidates (Linghu et al., 2...

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Section: Research Articlesupporting

confidence: 55%

Novel cardiovascular gene functions revealed via systematic phenotype prediction in zebrafish

et al. 2014

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“…hESCs were induced to differentiate with activin A and bone morphogenetic protein 4 (BMP4), in combination with sequential small molecule activation and inhibition of WNT/β-catenin signaling. Cells were then harvested as pluripotent hESCs (day 0), CPCs (day 5), or cardiomyocytes (day 14) (3,5,8) (Fig. 1A).…”

Section: Significancementioning

confidence: 99%

“…1A). We have previously shown that as cells differentiate toward CPCs, they express cardiac transcription factors, such as GATA binding protein 4 (GATA4), T-box 5 (TBX5), and NK2 homeobox 5 (NKX2.5) (3,8) (Fig. 1A).…”

Section: Significancementioning

confidence: 99%

“…Temporal overactivation or inhibition of the WNT/β-catenin signaling pathway has been shown to result in cardiac null phenotypes in vivo (4,6,7), because WNT/β-catenin is required to form mesoderm, and it subsequently must be repressed to form cardiomyocytes. Furthermore, overactivation of WNT/β-catenin signaling during hESC-derived cardiomyocyte differentiation results in a shift in mesoderm patterning to specify endothelium and early blood cells, but not cardiomyocytes (8). Conversely, inhibition of WNT/β-catenin has been shown to direct endocardial-like endothelial cells to differentiate toward the cardiac lineage (3).…”

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confidence: 99%

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Quantitative proteomics identify DAB2 as a cardiac developmental regulator that inhibits WNT/β-catenin signaling

Hofsteen

Robitaille

Chapman

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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To reveal the molecular mechanisms involved in cardiac lineage determination and differentiation, we quantified the proteome of human embryonic stem cells (hESCs), cardiac progenitor cells (CPCs), and cardiomyocytes during a time course of directed differentiation by label-free quantitative proteomics. This approach correctly identified known stage-specific markers of cardiomyocyte differentiation, including SRY-box2 (SOX2), GATA binding protein 4 (GATA4), and myosin heavy chain 6 (MYH6). This led us to determine whether our proteomic screen could reveal previously unidentified mediators of heart development. We identified Disabled 2 (DAB2) as one of the most dynamically expressed proteins in hESCs, CPCs, and cardiomyocytes. We used clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) mutagenesis in zebrafish to assess whether DAB2 plays a functional role during cardiomyocyte differentiation. We found that deletion of Dab2 in zebrafish embryos led to a significant reduction in cardiomyocyte number and increased endogenous WNT/β-catenin signaling. Furthermore, the Dab2-deficient defects in cardiomyocyte number could be suppressed by overexpression of dickkopf 1 (DKK1), an inhibitor of WNT/β-catenin signaling. Thus, inhibition of WNT/β-catenin signaling by DAB2 is essential for establishing the correct number of cardiomyocytes in the developing heart. Our work demonstrates that quantifying the proteome of human stem cells can identify previously unknown developmental regulators.

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“…TMEM88 has two isoforms: CRA-a (17 kDa) inhibits the canonical Wnt/b-catenin pathway by competing with low-density lipoprotein receptor-related proteins 5 and 6 to bind DVLS and regulates the development of myocardial cells, whereas CRA-b (25 kDa) lacks the VWV motif and may not interact with DVLS (7). The current understanding of the expression, subcellular location, and potential molecular mechanisms of TMEM88 is limited, particularly for malignant human cells.…”

Section: Introductionmentioning

confidence: 99%

Cytosolic TMEM88 Promotes Invasion and Metastasis in Lung Cancer Cells by Binding DVLS

Zhang

Jiang

et al. 2015

Cancer Research

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Transmembrane protein 88 (TMEM88) is a transmembrane protein that plays a crucial role in regulating human stem cell differentiation and embryonic development. However, its expression and clinicopathologic significance in human neoplasms is unclear. In this study, the expression and subcellular localizations of TMEM88 were assessed in 214 cases of non-small cell lung cancer (NSCLC). Notably, TMEM88 was highly expressed in the cytosol of $60% NSCLC specimens examined. Higher expression of cytosolic TMEM88 in NSCLC correlated significantly with poor differentiation, high TNM stage, lymph node metastasis, and inferior survival. In NSCLC cells displaying membrane-localized TMEM88, we observed an inhibition of canonical Wnt signaling due to interactions of TMEM88 with the Wnt pathway factor Dishevelled (DVLS). In contrast, NSCLC cells with cytosol-localized TMEM88 lacked effects on Wnt signaling. Cytosolic interactions of TMEM88 and DVLS increased the expression of phosphorylated, active forms of p38, GSK3b (Thr390), and Snail, thereby reducing the expression of the tight junction-associated proteins ZO-1 and occludin, effects associated with enhanced invasive and metastatic cell characters. Importantly, attenuating the expression of cytosolic TMEM88 reduced metastatic prowess in xenograft models. Overall, our findings show how mislocalization of TMEM88 to the cytosol in NSCLC cells ablates its Wnt pathway regulatory properties, thereby promoting invasion and metastasis by activating the p38-GSK3b-Snail signaling pathway. Cancer Res; 75(21); 4527-37. Ó2015 AACR.

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Transmembrane protein 88: a Wnt regulatory protein that specifies cardiomyocyte development

Cited by 58 publications

References 41 publications

Novel cardiovascular gene functions revealed via systematic phenotype prediction in zebrafish

Novel cardiovascular gene functions revealed via systematic phenotype prediction in zebrafish

Quantitative proteomics identify DAB2 as a cardiac developmental regulator that inhibits WNT/β-catenin signaling

Cytosolic TMEM88 Promotes Invasion and Metastasis in Lung Cancer Cells by Binding DVLS

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