Nkx2-5 and Sarcospan genetically interact in the development of the muscular ventricular septum of the heart

Panzer, Adam A; Regmi, Suk D.; Cormier, DePorres; Danzo, Megan T; Chen, Iuan-Bor D.; Winston, Julia B.; Hutchinson, Alayna K; Salm, Diana; Schulkey, Claire E.; Cochran, Rebecca; Wilson, David B.; Jay, Patrick Y.

doi:10.1038/srep46438

Cited by 7 publications

(5 citation statements)

References 50 publications

(74 reference statements)

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“…Thus, the cardiac defects observed in Jarid2 Nkx hearts are mainly caused by myocardial deletion of Jarid2, although we cannot exclude a possibility that Jarid2 may be deleted in a subset of endocardial cells. Nkx2.5-Cre mice are haploinsufficient for Nkx2.5, and Nkx2.5 haploinsufficiency is associated with atrial septal defects, VSD, and conduction system abnormalities albeit at a low rate in mouse models (45,46). Thus, we examined Nkx2.5-Cre (Nkx2.5-Cre/ ϩ;Jarid2ϩ/ϩ) and heterozygous (Nkx2.5-Cre/ϩ;Jarid2f/ϩ) mice for possible cardiac defects.…”

Section: Cardiac Development and Jarid2mentioning

confidence: 99%

Cardiac-specific developmental and epigenetic functions of Jarid2 during embryonic development

Cho

Mysliwiec

Carlson

et al. 2018

Journal of Biological Chemistry

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Epigenetic regulation is critical in normal cardiac development. We have demonstrated that the deletion of (Jumonji (Jmj) A/T-rich interaction domain 2) in mice results in cardiac malformations recapitulating human congenital cardiac disease and dysregulation of gene expression. However, the precise developmental and epigenetic functions of Jarid2 within the developing heart remain to be elucidated. Here, we determined the cardiac-specific functions of Jarid2 and the genetic networks regulated by Jarid2. was deleted using different cardiac-specific Cre mice. The deletion of by mice () caused cardiac malformations including ventricular septal defects, thin myocardium, hypertrabeculation, and neonatal lethality. mice exhibited elevated expression of neural genes, cardiac jelly, and other key factors including Isl1 and Bmp10 in the developing heart. By employing combinatorial genome-wide approaches and molecular analyses, we showed that Jarid2 in the myocardium regulates a subset of Jarid2 target gene expression and H3K27me3 enrichment during heart development. Specifically, Jarid2 was required for PRC2 occupancy and H3K27me3 at the promoter locus, leading to the proper repression of expression. In contrast, deletion in differentiated cardiomyocytes by mice caused no gross morphological defects or neonatal lethality. Thus, the early deletion of in cardiac progenitors, prior to the differentiation of cardiac progenitors into cardiomyocytes, results in morphogenetic defects manifested later in development. Our studies reveal that there is a critical window during early cardiac progenitor differentiation when Jarid2 is crucial to establish the epigenetic landscape at later stages of development.

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Section: Cardiac Development and Jarid2mentioning

confidence: 99%

Cardiac-specific developmental and epigenetic functions of Jarid2 during embryonic development

Cho

Mysliwiec

Carlson

et al. 2018

Journal of Biological Chemistry

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“…The understanding of the molecular processes that trigger the formation of the muscular interventricular septum are scarce, beyond the fact that both right and left ventricular myocytes contribute to it [437] and that Tbx5 and eHand play a fundamental role directing the precise position of the interventricular septum (IVS) [201,438] (Table 1). Similarly, our understanding of the molecular mechanisms driving the mesenchymal contribution are also scarce, even most IVS septal defects lack proper development of this mesenchymal component [439,440] and scarce evidence are reported affecting the muscular component [441].…”

Section: Ventricular Septationmentioning

confidence: 99%

Cardiac Development: A Glimpse on Its Translational Contributions

Franco

García-Padilla

Domínguez

et al. 2021

Hearts

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Cardiac development is a complex developmental process that is initiated soon after gastrulation, as two sets of precardiac mesodermal precursors are symmetrically located and subsequently fused at the embryonic midline forming the cardiac straight tube. Thereafter, the cardiac straight tube invariably bends to the right, configuring the first sign of morphological left–right asymmetry and soon thereafter the atrial and ventricular chambers are formed, expanded and progressively septated. As a consequence of all these morphogenetic processes, the fetal heart acquired a four-chambered structure having distinct inlet and outlet connections and a specialized conduction system capable of directing the electrical impulse within the fully formed heart. Over the last decades, our understanding of the morphogenetic, cellular, and molecular pathways involved in cardiac development has exponentially grown. Multiples aspects of the initial discoveries during heart formation has served as guiding tools to understand the etiology of cardiac congenital anomalies and adult cardiac pathology, as well as to enlighten novels approaches to heal the damaged heart. In this review we provide an overview of the complex cellular and molecular pathways driving heart morphogenesis and how those discoveries have provided new roads into the genetic, clinical and therapeutic management of the diseased hearts.

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“…Since β-adrenergic receptor expression was maintained-the lack of functional responsiveness may be attributed to other mechanisms that include altered cardiomyocyte Ca 2+ handling. Overall, this study is aimed at understanding the normal functions of SSPN in the developing and adult heart that protect the heart from injury and arrhythmias [15,16].…”

Section: Introductionmentioning

confidence: 99%

Sarcospan Deficiency Increases Oxidative Stress and Arrhythmias in Hearts after Acute Ischemia-Reperfusion Injury

Hwang,

Kahmini,

Prascak

et al. 2023

IJMS

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The protein sarcospan (SSPN) is an integral member of the dystrophin-glycoprotein complex (DGC) and has been shown to be important in the heart during the development and the response to acute stress. In this study, we investigated the role of SSPN in the cardiac response to acute ischemia-reperfusion (IR) injury in SSPN-deficient (SSPN−/−) mice. First, the hemodynamic response of SSPN−/− mice was tested and was similar to SSPN+/+ (wild-type) mice after isoproterenol injection. Using the in situ Langendorff perfusion method, SSPN−/− hearts were subjected to IR injury and found to have increased infarct size and arrhythmia susceptibility compared to SSPN+/+. Ca2+ handling was assessed in single cardiomyocytes and diastolic Ca2+ levels were increased after acute β-AR stimulation in SSPN+/+ but not SSPN−/−. It was also found that SSPN−/− cardiomyocytes had reduced Ca2+ SR content compared to SSPN+/+ but similar SR Ca2+ release. Next, we used qRT-PCR to examine gene expression of Ca2+ handling proteins after acute IR injury. SSPN−/− hearts showed a significant decrease in L-type Ca2+ channels and a significant increase in Ca2+ release channel (RyR2) expression. Interestingly, under oxidizing conditions reminiscent of IR, SSPN−/− cardiomyocytes, had increased H2O2-induced reactive oxygen species production compared to SSPN+/+. Examination of oxidative stress proteins indicated that NADPH oxidase 4 and oxidized CAMKII were increased in SSPN−/− hearts after acute IR injury. These results suggest that increased arrhythmia susceptibility in SSPN−/− hearts post-IR injury may arise from alterations in Ca2+ handling and a reduced capacity to regulate oxidative stress pathways.

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Nkx2-5 and Sarcospan genetically interact in the development of the muscular ventricular septum of the heart

Cited by 7 publications

References 50 publications

Cardiac-specific developmental and epigenetic functions of Jarid2 during embryonic development

Cardiac-specific developmental and epigenetic functions of Jarid2 during embryonic development

Cardiac Development: A Glimpse on Its Translational Contributions

Sarcospan Deficiency Increases Oxidative Stress and Arrhythmias in Hearts after Acute Ischemia-Reperfusion Injury

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