Bmp2 and Gata4 function additively to rescue heart tube development in the absence of retinoids

Ghatpande, Satish; Brand, Thomas; Zile, Maija H.; Evans, Todd

doi:10.1002/dvdy.20836

Cited by 15 publications

(15 citation statements)

References 52 publications

(66 reference statements)

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“…Whether this interference contributes to HPV-related pathogenesis is unclear, yet it may offer novel treatment options. A common feature of the 5 methylation signature genes identified in our study is their involvement in tissue development and regeneration, and 4 of them, ALDH1A2, OSR2, GATA4, and IRX4, are related to retinoid metabolism and signaling (25,26,(68)(69)(70)(71)(72)(73)(74). Since retinoic acids exert potent effects on cell growth, differentiation, and apoptosis, targeting one or a combination of the 4 genes and thereby modulating retinoid metabolism and signaling may offer novel avenues in successful treatment of OPSCC (75,76).…”

Section: Discussionmentioning

confidence: 73%

HPV-related methylation signature predicts survival in oropharyngeal squamous cell carcinomas

Kostareli¹,

Holzinger²,

Bogatyrova³

et al. 2013

J. Clin. Invest.

111

130

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High-risk types of human papilloma virus (HPV) are increasingly associated with oropharyngeal squamous cell carcinoma (OPSCC). Strikingly, patients with HPV-positive OPSCC are highly curable with ionizing radiation and have better survival compared with HPV-negative patients, but the underlying molecular mechanisms remain poorly understood. We applied an array-based approach to monitor global changes in CpG island hypermethylation between HPV-negative and HPV-positive OPSCCs and identified a specific pattern of differentially methylated regions that critically depends on the presence of viral transcripts. HPV-related alterations were confirmed for the majority of candidate gene promoters by mass spectrometric, quantitative methylation analysis. There was a significant inverse correlation between promoter hypermethylation of ALDH1A2, OSR2, GATA4, GRIA4, and IRX4 and transcript levels. Interestingly, Kaplan-Meier analysis revealed that a combined promoter methylation pattern of low methylation levels in ALDH1A2 and OSR2 promoters and high methylation levels in GATA4, GRIA4, and IRX4 promoters was significantly correlated with improved survival in 3 independent patient cohorts. ALDH1A2 protein levels, determined by immunohistochemistry on tissue microarrays, confirmed the association with clinical outcome. In summary, our study highlights specific alterations in global gene promoter methylation in HPV-driven OPSCCs and identifies a signature that predicts the clinical outcome in OPSCCs.

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Section: Discussionmentioning

confidence: 73%

HPV-related methylation signature predicts survival in oropharyngeal squamous cell carcinomas

Kostareli¹,

Holzinger²,

Bogatyrova³

et al. 2013

J. Clin. Invest.

111

130

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“…More likely it is the feedback repression that Nkx2.5 normally imposes on Bmp2/ Smad signaling (31), which when relieved may improve the RA deficiency phenotype. Transplantation of W T foregut endoderm, or exogenous supply of BMP2 and Gata4, can restore heart morphology in vitamin A-deficient quail embryos (35,36). Although Bmp2 expression indeed appears up-regulated in Nkx2.5;Raldh2 compound mutants, further genetic strategies are required to clarify the precise manner by which these two signaling pathways interact.…”

Section: Discussionmentioning

confidence: 99%

Retinoic acid deficiency alters second heart field formation

Ryckebüsch

Wang

Bertrand

et al. 2008

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

195

240

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Retinoic acid (RA), the active derivative of vitamin A, has been implicated in various steps of cardiovascular development. The retinaldehyde dehydrogenase 2 (RALDH2) enzyme catalyzes the second oxidative step in RA biosynthesis and its loss of function creates a severe embryonic RA deficiency. Raldh2 ؊/؊ knockout embryos fail to undergo heart looping and have impaired atrial and sinus venosus development. To understand the mechanism(s) producing these changes, we examined the contribution of the second heart field (SHF) to pharyngeal mesoderm, atria, and outflow tract in Raldh2 ؊/؊ embryos. RA deficiency alters SHF gene expression in two ways. First, Raldh2 ؊/؊ embryos exhibited a posterior expansion of anterior markers of the SHF, including Tbx1, Fgf8, and the Mlc1v-nlacZ-24/Fgf10 reporter transgene as well as of Islet1. This occurred at early somite stages, when cardiac defects became irreversible in an avian vitamin A-deficiency model, indicating that endogenous RA is required to restrict the SHF posteriorly. Explant studies showed that this expanded progenitor population cannot differentiate properly. Second, RA up-regulated cardiac Bmp expression levels at the looping stage. The contribution of the SHF to both inflow and outflow poles was perturbed under RA deficiency, creating a disorganization of the heart tube. We also investigated genetic cross-talk between Nkx2.5 and RA signaling by generating double mutant mice. Strikingly, Nkx2.5 deficiency was able to rescue molecular defects in the posterior region of the Raldh2 ؊/؊ mutant heart, in a gene dosage-dependent manner.retinoids ͉ retinaldehyde dehydrogenase 2 ͉ heart development ͉ Nkx2.5 ͉ FGF8

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“…Gata4 is expressed most strongly at the 5 somite stage in the region of the presumptive inflow tract and posterior heart tube, and this is precisely the region that fails to develop normally in the VAD embryo. Studies showed that VAD results in reduced expression of Bmp2 throughout the sino-atrial region [59]. Furthermore, addition of exogenous Bmp2 can function additively with forced expression of Gata4 to overcome the loss of retinoid signaling, indicating the presence of an active RA-BMP-GATA network for posterior heart tube development.…”

Section: Retinoic Acid and Early Heart Developmentmentioning

confidence: 99%

Retinoids and Cardiac Development

Zaffran

Robrini

Bertrand

2014

JDB

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Retinoic acid (RA), a derivative of vitamin A, is involved in signal transduction during vertebrate organogenesis. Retinoids through binding to nuclear receptors called RA receptors (RARs) and retinoid X receptors (RXRs) regulate various processes during cardiogenesis. Deregulated retinoid signaling thus has later consequences leading to cardiac malformations. In this review, we will summarize and discuss our current knowledge on the role of RA signaling during heart development, especially during patterning of the heart fields. We have also integrated recent experiments essential for our understanding of the role of RA signaling during epicardial development and myocardial growth.

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Bmp2 and Gata4 function additively to rescue heart tube development in the absence of retinoids

Cited by 15 publications

References 52 publications

HPV-related methylation signature predicts survival in oropharyngeal squamous cell carcinomas

HPV-related methylation signature predicts survival in oropharyngeal squamous cell carcinomas

Retinoic acid deficiency alters second heart field formation

Retinoids and Cardiac Development

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