Nkx2-5 Pathways and Congenital Heart Disease

Abstract

Human mutations in Nkx2-5 lead to progressive cardiomyopathy and conduction defects via unknown mechanisms. To define these pathways, we generated mice with a ventricular-restricted knockout of Nkx2-5, which display no structural defects but have progressive complete heart block, and massive trabecular muscle overgrowth found in some patients with Nkx2-5 mutations. At birth, mutant mice display a hypoplastic atrioventricular (AV) node and then develop selective dropout of these conduction cells. Transcriptional profiling uncovered the aberrant expression of a unique panel of atrial and conduction system-restricted target genes, as well as the ectopic, high level BMP-10 expression in the adult ventricular myocardium. Further, BMP-10 is shown to be necessary and sufficient for a major component of the ventricular muscle defects. Accordingly, loss of ventricular muscle cell lineage specification into trabecular and conduction system myocytes is a new mechanistic pathway for progressive cardiomyopathy and conduction defects in congenital heart disease.

Cardiac-specific elevations in thyroid hormone enhance contractility and prevent pressure overload-induced cardiac dysfunction

“…Indeed, reduced expression of SERCA2a, along with impaired Ca 2ϩ transients and SR Ca 2ϩ uptake rates induced by pressure overload, were completely ameliorated in D2 transgenic mice, consistent with the beneficial effects of restored SERCA2a͞PLN ratios in heart disease (41). Some of the protection could also be related to SLN, consistent with recent studies showing elevated SLN in the diseased heart (42).…”

BMP10 is essential for maintaining cardiac growth during murine cardiogenesis

“…A recent related study by Pashmforoush et al (Pashmforoush et al, 2004) has indicated that Nkx2.5 can act as a negative-feedback regulator of BMP10 expression at later developmental stages. Mutant mice with a late onset cardiomyocyte-specific Nkx2.5 null mutation, generated via a conditional cre/loxP knockout strategy, have an abnormal myocardium with increased ventricular trabeculation.…”

Tinman/Nkx2-5 acts via miR-1 and upstream of Cdc42 to regulate heart function across species

“…Mouse models of Nkx2-5 deficiency revealed a critical role for Nkx2-5 in establishing and maintaining proper cardiac conduction system function (Pashmforoush et al, 2004;Briggs et al, 2008;Takeda et al, 2009), and human mutations in Nkx2-5 cause conduction-system dysfunction (Schott et al, 1998). Given the interaction between tinman and Cdc42 that we identified in the fly, we hypothesized that Nkx2-5 also interacts with Cdc42 in regulating the electrical activity of adult mouse heart.…”

“…Whereas ablation of tinman in the Drosophila embryo abolishes heart formation, targeted deletion of tinman at later stages reveals additional requirements for tinman in maintaining normal adult heart function and physiology (Zaffran et al, 2006). This is reminiscent of Nkx2-5 in vertebrates, which is required for establishing heart function in the developing mouse embryo, for example, and also later for its maintenance in the adult (Pashmforoush et al, 2004). The genetic networks that Nkx2-5 participates in and how these interactions regulate adult heart functions are not well understood.…”