GATA6 Regulates Aortic Valve Remodeling, and Its Haploinsufficiency Leads to Right-Left Type Bicuspid Aortic Valve

Gharibeh, Lara; Komati, Hiba; Bossé, Yohan; Boodhwani, Munir; Heydarpour, Mahyar; Fortier, Megan; Hassanzadeh, Romina; Ngu, Janet M.C.; Mathieu, Patrick; Body, Simon C.; Nemer, Mona

doi:10.1161/circulationaha.117.029506

Cited by 74 publications

(88 citation statements)

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“…This phenotype was shown to result from a defective septation process including abnormal extracellular matrix degradation and cell death. Deletion of one allele of Gata6 from SHF‐derived cells recapitulates the phenotype observed in Gata6 heterozygous mice . Conditional inactivation of Gata6 from neural crest cells or vascular smooth muscle cells led to OFT defects (mainly PTA) and lethality by E18.5‐P2, revealing an important role for GATA6 in the formation of the OFT and the aortic arch .…”

Section: Role Of Cardiac Gata Factors In Embryonic Developmentmentioning

confidence: 55%

“…GATA6 plays an essential role in the growth of a population of cells important for the generation of the extraembryonic tissues in the developing blastocyst and Gata6 null mice die embryonically due to extraembryonic defects and problems with visceral endoderm function . Recent work has shown that Gata6 heterozygous mice have high incidence of RL‐type BAV, the most common BAV diagnosed in humans . This phenotype was shown to result from a defective septation process including abnormal extracellular matrix degradation and cell death.…”

Section: Role Of Cardiac Gata Factors In Embryonic Developmentmentioning

confidence: 99%

“…28 Recent work has shown that Gata6 heterozygous mice have high incidence of RL-type BAV, the most common BAV diagnosed in humans. 29 This phenotype was shown to result from a defective septation process including abnormal extracellular matrix degradation and cell death. Deletion of one allele of Gata6 from SHF-derived cells recapitulates the phenotype observed in Gata6 heterozygous mice.…”

Section: Gata6mentioning

confidence: 99%

“…Deletion of one allele of Gata6 from SHF-derived cells recapitulates the phenotype observed in Gata6 heterozygous mice. 29 Conditional inactivation of Gata6 from neural crest cells or vascular smooth muscle cells led to OFT defects (mainly PTA) and lethality by E18.5-P2, revealing an important role for GATA6 in the formation of the OFT and the aortic arch. 30 Cell-specific knockout of Gata6 from endothelial cells (VE-Cadherin-Cre) and myocardial cells (Nkx2.5and BMHC-Cre) also leads to a large spectrum of cardiac defects, mainly septation defects.…”

Section: Gata6mentioning

confidence: 99%

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From embryogenesis to adulthood: Critical role for GATA factors in heart development and function

2019

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Cardiac development is governed by a complex network of transcription factors (TFs) that regulate cell fates in a spatiotemporal manner. Among these, the GATA family of zinc finger TFs plays prominent roles in regulating the development of the myocardium, endocardium, and outflow tract. This family comprises six members three of which, GATA4, 5, and 6, are predominantly expressed in cardiac cells where they activate specific downstream gene targets via interactions with one another and with other TFs and signaling molecules. Their critical function in heart formation is evidenced by the phenotypes of animal models lacking these factors and by the broad spectrum of human congenital heart diseases associated with mutations in their genes. Similarly, in the postnatal heart, these proteins play significant and nonredundant roles in cardiac function, regulating adaptive stress responses including cardiomyocyte hypertrophy and survival, as well as endothelial homeostasis and angiogenesis. As such, decreased expression of either GATA4, 5, or 6 results in impaired cardiovascular homeostasis and increased risk of premature and serious cardiovascular events such as hypertension, arrhythmia, aortopathy, and heart failure. Although a great deal of progress has been made in understanding GATA‐dependent regulatory processes in the heart, the molecular mechanisms underlying the specificity of GATA factors and their upstream regulation remain incompletely understood. The knowledge and tools developed since their discovery 25 years ago should accelerate progress toward further elucidation of their mechanisms of action in health and disease. This in turn will greatly improve diagnosis and care for the millions of individuals affected by congenital and acquired cardiac disease worldwide.

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Section: Role Of Cardiac Gata Factors In Embryonic Developmentmentioning

confidence: 55%

Section: Role Of Cardiac Gata Factors In Embryonic Developmentmentioning

confidence: 99%

Section: Gata6mentioning

confidence: 99%

Section: Gata6mentioning

confidence: 99%

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From embryogenesis to adulthood: Critical role for GATA factors in heart development and function

2019

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“…The Gata6‐positive population does not originate from Shh‐positive progenitors (Mesler et al , ) and an alternative possibility is that it arises from Sox9 progenitors (Fig A). Regulation of Sox9 by Gata6 has been shown in several organs, including the pancreas (Carrasco et al , ) and cardiac valves (Gharibeh et al , ).…”

Section: Discussionmentioning

confidence: 99%

Mutant Lef1 controls Gata6 in sebaceous gland development and cancer

et al. 2019

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Mutations in Lef1 occur in human and mouse sebaceous gland (SG) tumors, but their contribution to carcinogenesis remains unclear. Since Gata6 controls lineage identity in SG, we investigated the link between these two transcription factors. Here, we show that Gata6 is a β‐catenin‐independent transcriptional target of mutant Lef1. During epidermal development, Gata6 is expressed in a subset of Sox9‐positive Lef1‐negative hair follicle progenitors that give rise to the upper SG. Overexpression of Gata6 by in utero lentiviral injection is sufficient to induce ectopic sebaceous gland elements. In mice overexpressing mutant Lef1, Gata6 ablation increases the total number of skin tumors yet decreases the proportion of SG tumors. The increased tumor burden correlates with impaired DNA mismatch repair and decreased expression of Mlh1 and Msh2 genes, defects frequently observed in human sebaceous neoplasia. Gata6 specifically marks human SG tumors and also defines tumors with elements of sebaceous differentiation, including a subset of basal cell carcinomas. Our findings reveal that Gata6 controls sebaceous gland development and cancer.

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Novel Association of the NOTCH Pathway Regulator MIB1 Gene With the Development of Bicuspid Aortic Valve

Tessler,

Albuisson,

Piñeiro-Sabarís

et al. 2023

JAMA Cardiol

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ImportanceNonsyndromic bicuspid aortic valve (nsBAV) is the most common congenital heart valve malformation. BAV has a heritable component, yet only a few causative genes have been identified; understanding BAV genetics is a key point in developing personalized medicine.ObjectiveTo identify a new gene for nsBAV.Design, Setting, and ParticipantsThis was a comprehensive, multicenter, genetic association study based on candidate gene prioritization in a familial cohort followed by rare and common association studies in replication cohorts. Further validation was done using in vivo mice models. Study data were analyzed from October 2019 to October 2023. Three cohorts of patients with BAV were included in the study: (1) the discovery cohort was a large cohort of inherited cases from 29 pedigrees of French and Israeli origin; (2) the replication cohort 1 for rare variants included unrelated sporadic cases from various European ancestries; and (3) replication cohort 2 was a second validation cohort for common variants in unrelated sporadic cases from Europe and the US.Main Outcomes and MeasuresTo identify a candidate gene for nsBAV through analysis of familial cases exome sequencing and gene prioritization tools. Replication cohort 1 was searched for rare and predicted deleterious variants and genetic association. Replication cohort 2 was used to investigate the association of common variants with BAV.ResultsA total of 938 patients with BAV were included in this study: 69 (7.4%) in the discovery cohort, 417 (44.5%) in replication cohort 1, and 452 (48.2%) in replication cohort 2. A novel human nsBAV gene, MINDBOMB1 homologue MIB1, was identified. MINDBOMB1 homologue (MIB1) is an E3-ubiquitin ligase essential for NOTCH-signal activation during heart development. In approximately 2% of nsBAV index cases from the discovery and replication 1 cohorts, rare MIB1 variants were detected, predicted to be damaging, and were significantly enriched compared with population-based controls (2% cases vs 0.9% controls; P = .03). In replication cohort 2, MIB1 risk haplotypes significantly associated with nsBAV were identified (permutation test, 1000 repeats; P = .02). Two genetically modified mice models carrying Mib1 variants identified in our cohort showed BAV on a NOTCH1-sensitized genetic background.Conclusions and RelevanceThis genetic association study identified the MIB1 gene as associated with nsBAV. This underscores the crucial role of the NOTCH pathway in the pathophysiology of BAV and its potential as a target for future diagnostic and therapeutic intervention.

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GATA6 Regulates Aortic Valve Remodeling, and Its Haploinsufficiency Leads to Right-Left Type Bicuspid Aortic Valve

Abstract: The data identify a new cellular and molecular mechanism underlying BAV. The availability of an animal model for the most frequent human BAV opens the way for the elucidation of BAV pathogenesis and the development of much needed therapies.

Cited by 74 publications

References 47 publications

From embryogenesis to adulthood: Critical role for GATA factors in heart development and function

From embryogenesis to adulthood: Critical role for GATA factors in heart development and function

Mutant Lef1 controls Gata6 in sebaceous gland development and cancer

Novel Association of the NOTCH Pathway Regulator MIB1 Gene With the Development of Bicuspid Aortic Valve

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