The Homeodomain Transcription Factor Irx5 Establishes the Mouse Cardiac Ventricular Repolarization Gradient

Abstract

Rhythmic cardiac contractions depend on the organized propagation of depolarizing and repolarizing wavefronts. Repolarization is spatially heterogeneous and depends largely on gradients of potassium currents. Gradient disruption in heart disease may underlie susceptibility to fatal arrhythmias, but it is not known how this gradient is established. We show that, in mice lacking the homeodomain transcription factor Irx5, the cardiac repolarization gradient is abolished due to increased Kv4.2 potassium-channel expression in endocardial myocardium, resulting in a selective increase of the major cardiac repolarization current, I(to,f), and increased susceptibility to arrhythmias. Myocardial Irx5 is expressed in a gradient opposite that of Kv4.2, and Irx5 represses Kv4.2 expression by recruiting mBop, a cardiac transcriptional repressor. Thus, an Irx5 repressor gradient negatively regulates potassium-channel-gene expression in the heart, forming an inverse I(to,f) gradient that ensures coordinated cardiac repolarization while also preventing arrhythmias.

Iroquois homeobox gene 3 establishes fast conduction in the cardiac His–Purkinje network

“…We have shown that Irx5 represses transcription of the voltage-gated potassium channel gene Kv4.2 to establish an epicardial-to-endocardial repolarization gradient (12)(13)(14)(15)(16). Our present study identifies a previously undescribed role for an additional Iroquois factor, Irx3, in the tight regulation of gap junction gene expression in specialized HisPurkinje system cells, where its expression is highly enriched.…”

“…In the proximal VCS, where these transcription factors at expressed at high levels, Irx3 could therefore repress Nkx2-5-mediated activation of Gja1 transcription. Furthermore, direct binding of Irx3 to the Gja1 promoter may lead to transcriptional repression through its interactions with Nkx2-5 or Tbx5 and/or through recruitment of corepressors through a mechanism similar to that of Irx5 (13).…”

“…Irx genes have evolutionarily conserved roles during embryonic development (10) and can act as either repressors or activators of gene expression depending on the cellular context (11)(12)(13). All six Irx genes are expressed in partially overlapping patterns in the developing mouse heart (12)(13)(14)(15)(16).…”

The prepattern transcription factor Irx3 directs nephron segment identity

“…This notion was confirmed as blocking of irx1 and irx2 translation either alone or together did not affect nephron patterning and differentiation in Xenopus. Redundant roles for Irx genes have also been reported in the mouse, where the loss of function of Irx genes does not significantly affect embryonic development (Bruneau et al 2001;Lebel et al 2003;Costantini et al 2005). In contrast, knockdown of Xenopus irx3 function caused a profound patterning defect in the developing pronephric nephron manifesting in the deletion of segments spanning from PT3 to IT2.…”

“…In the mouse, expression persists in the thick limbs (S3 and TAL) but not in the thin limbs of Henle (DTL and ATL). Interestingly, direct evidence for a late function of Irx genes was recently provided by studies of Irx5-deficient mice, where Irx5 maintains asymmetric potassium channel expression (Costantini et al 2005). Thus, Irx genes may serve as determining factors in the developing nephron and subsequently as maintenance factors ensuring persistent segment-specific gene expression in the mature nephron.…”