Cyclin D₂ rescues size and function of GATA4 haplo-insufficient hearts

Abstract

Transcription factor GATA4 is a key regulator of cardiomyocyte growth, and differentiation and 50% reduction in GATA4 levels results in hypoplastic hearts. Search for GATA4 targets/effectors revealed cyclin D(2) (CD2), a member of the D-type cyclins (D(1), D(2), and D(3)) that play a vital role in cell growth and differentiation as a direct transcriptional target and a mediator of GATA4 growth in postnatal cardiomyocytes. GATA4 associates with the CD2 promoter in cardiomyocytes and is sufficient to induce endogenous CD2 transcription and to dose-dependently activate the CD2 promoter in heterologous cells. Cardiomyocyte-specific overexpression of CD2 results in enhanced postnatal cardiac growth because of increased cardiomyocyte proliferation. When these transgenic mice are crossed with Gata4 heterozygote mice, they rescue the hypoplastic cardiac phenotype of Gata4(+/-) mice and enhance cardiomyocyte survival and heart function. The data uncover a role for CD2 in the postnatal heart as an effector of GATA4 in myocyte growth and survival. The finding that postnatal upregulation of a cell-cycle gene in GATA4 haplo-insufficient hearts may be protective opens new avenues for maintaining or restoring cardiac function in GATA4-dependent cardiac disease.

Cyclin D2 is a GATA4 cofactor in cardiogenesis

“…1D, CycD2 was enriched twofold on the −99 GATA site relative to the Dessert gene (used as internal control). GATA4 was also enriched at this site, consistent with our previous results (18).…”

“…Quantitative PCR analysis confirmed that ccnd2 transcripts are specifically up-regulated in the heart but have no effect on GATA4 encoding mRNA levels (Fig. 1C), consistent with our published results (18). Up-regulation of ccnd2 resulted in a twofold higher GATA-dependent luciferase transcription specifically in the heart of double transgenics but not in other organs exhibiting GATA activity like liver (Fig.…”

“…CycD2 is a direct GATA4 target in the heart (18,19), where it is coexpressed with GATA4 in fetal and neonate cardiomyocytes. In the mouse heart, CycD2 transcripts have been reported as early as embryonic day (E) 9 in the developing ventricles (23).…”

“…The production of transgenic mice homozygous for one or more Cyclin D allele has confirmed the requirement for specific Cyclin Ds in organ development (17). CycD2 appears to play an important role in the embryonic and postnatal heart, where it has been shown to be a direct target of the cardiogenic transcription factor GATA4 (18,19). CycD2 has been linked to cardiomyocyte regeneration (20), hypertrophy (21), and stress response (22).…”

ASK1 mediates the teratogenicity of diabetes in the developing heart by inducing ER stress and inhibiting critical factors essential for cardiac development

“…Cyclin D2 is a GATA4 cofactor in cardiogenesis (54); however, we did not observe any changes in cyclin D2 expression. In the neonatal heart, GATA4 induces cyclin D2 transcription (55). In our study, reduced GATA4 expression does not cause cyclin D2 downregulation.…”