Hopx and the Cardiomyocyte Parentage

Abstract

The dissection of steps that pattern primitive mesoderm toward the cardiovascular lineages is important to our current understanding of cardiovascular development and can instruct regenerative approaches to heart repair.1 Primitive precursors that can adopt a cardiovascular fate, but also a subset of other mesoderm, are marked by the transcription factor Mesp1 (refs. 2, 3). Later precursors, which selectively give rise to two or more of the cardiovascular cell types (bi- and multipotent cardiovascular progenitor cells), are marked by the transcription factors Nkx2.5 or Isl1, indicators of the first and second heart-forming regions of the embryo (“heart fields”).4,5,6 What has been missing, however, is a molecular feature that uniquely marks cells destined to become cardiomyocytes within the heart. To illustrate, mapping the descendants of cells expressing either Nkx2.5 or Isl1, using the Cre/lox system to indelibly label their progeny in vivo, marks virtually all cell types of the mature heart, including smooth muscle, endothelium, epicardium, and fibroblasts.1 This ubiquity results from expression of Nkx2.5 and Isl1 in the proepicardial organ,7 a specialized structure on the surface of the early heart that gives rise to the external lining of the heart (epicardium) and its derivatives (coronary smooth muscle, coronary endothelial cells, cardiac fibroblasts). In short, what is missing is a marker of the immediate and specific precursor of cardiomyocytes, rather than earlier multipotent cells. A recent report by Jain et al. now shows that an atypical homeodomain transcription factor, Hopx, lacking a motif for direct DNA binding, is restricted to the direct precursors of cardiomyocytes, and not to those of the various other cardiac cells.8