Mesp1 Patterns Mesoderm into Cardiac, Hematopoietic, or Skeletal Myogenic Progenitors in a Context-Dependent Manner

Abstract

Summary Mesp1 is regarded as the master regulator of cardiovascular development, initiating the cardiac transcription factor cascade to direct the generation of cardiac mesoderm. To define the early embryonic cell population that responds to Mesp1, we performed pulse inductions of gene expression over tight temporal windows following embryonic stem cell differentiation. Remarkably, instead of promoting cardiac differentiation in the initial wave of mesoderm, Mesp1 binds to the Tal1 (Scl) +40k enhancer and generates Flk-1+ precursors expressing Etv2 (ER71) and Tal1 that undergo hematopoietic differentiation. The second wave of mesoderm responds to Mesp1 by differentiating into PDGFRα+ precursors that undergo cardiac differentiation. Furthermore, in the absence of serum-derived factors, Mesp1 promotes skeletal myogenic differentiation. Lineage tracing revealed that the majority of yolk sac and many adult hematopoietic cells derive from Mesp1+ precursors. Thus, Mesp1 is a context-dependent determination factor, integrating stage of differentiation and signaling environment to specify different lineage outcomes.

Id genes are essential for early heart formation

“…Among them, Mesp1 is the earliest expressed and is sufficient to directly promote cardiac specification in mesoderm progenitors (Saga et al 1996;Bondue et al 2008;David et al 2008;Chan et al 2013). Importantly, our gain-of-function experiments show that Id1/Xid2 is sufficient to direct Mesp1/Xmespb expression in both mESCs and hESCs as well as in Xenopus embryos and subsequently promote cardiogenic mesoderm differentiation.…”

“…Although these observations suggest that Mesp1/2 genes could act as master regulators of multipotent cardiovascular specification, retrospective lineage analysis (Saga et al 2000;Yoshida et al 2008) and in vitro differentiation studies (Chan et al 2013) have shown that Mesp1-expressing cells also contribute to a wide range of noncardiac derivatives, including hematopoietic precursors, skeletal muscle cells, and head mesenchyme. Therefore, additional effectors responsible for specifying cardiac cell fate remain to be discovered.…”

The force within: endocardial development, mechanotransduction and signalling during cardiac morphogenesis

“…Further support for a common, multipotent myocardial-endocardial progenitor stems from analyses in mouse and zebrafish that demonstrated an important role for the cardiac transcriptional regulator NK2 homeobox 5 (Nkx2.5) in directly inducing the endothelial factor Etv2, highlighting that a key cardiac regulatory factor is required for initiating endothelial and endocardial differentiation programmes (Akazawa and Komuro, 2005;Ferdous et al, 2009;Lints et al, 1993). Lineage tracing of mesoderm posterior 1 (Mesp1) + cells, which contribute to a wide range of mesodermal fates including the cardiac lineages (Chan et al, 2013;Yoshida et al, 2008), indicated that although most cardiac progenitors become lineage restricted as early as gastrulation in the mouse embryo, a small portion (<5%) contribute to multiple lineages, including myocardium and endocardium (Devine et al, 2014), providing further evidence for the 'multipotent progenitor' model. Although further studies are needed to fully understand the origins of the endocardium, one way of reconciling the 'pre-specification' and 'multipotent progenitor' models may be to assume that cardiogenic progenitors remain multipotent throughout cardiac crescent stages, but that positional information influences their fates (Harris and Black, 2010).…”

How to make a cardiomyocyte

“…Bvht further mediates epigenetic changes that facilitate cardiac lineage specification. Mesp1 is not specific to the cardiogenic mesoderm, as Mesp1-Cre lineage tracing also demonstrated its contribution to other mesodermal-derived populations in the embryo, but it is crucial for cardiac development (Chan et al, 2013). An Mesp1 mutation results in cardia bifida and Mesp1 and Mesp2 double-mutant cells fail to contribute to the forming heart (Kitajima et al, 2000).…”