Further Development 18.5: A Gene Regulatory Network at the Heart of Cardiogenic Mesoderm Specification

Intermediate and Lateral Plate Mesoderm: Heart, Blood, and Kidneys

In the absence of Wnt signals, BMPs activate Nkx2-5 and Mesp1, two genes that are critical in the regulatory network that specifies the heart cells (Figure 1). The Nkx2-5 gene has functions in heart development that are conserved across species (Komuro and Izumo 1993; Lints et al. 1993; Sugi and Lough 1994; Schultheiss et al. 1995; Andrée et al. 1998). The Nkx2-5 homologue in Drosophila is called tinman, as loss-of-function mutants lack a heart. Nkx2-5 can also downregulate BMPs, and in early heart cell development it limits the number of heart cell precursors that can form the heart fields. If the Nkx2-5 gene is specifically knocked out in those cells destined to become ventricles, these chambers express BMP10, resulting in massive overgrowth of the ventricles such that the ventricular chambers fill with muscle cells (Pashmforoush et al. 2004; Prall et al. 2007).

The other gene activated by BMPs is Mesp1.1 Mesp1 and Nkx2-5 proteins cooperate to activate the genes that specify the heart. Mesp1 also acts to prevent heart progenitors from being respecified as some other type of mesoderm. First, it activates the Dickkopf gene in the heart progenitors (David et al. 2008), thereby preventing Wnts from transforming these cells into vascular cells. Second, Mesp1 represses Brachyury, Sox17, and Goosecoid genes so the cardiac precursor cells will not become endoderm, somite, or notochord (Bondue and Blanpain 2010). Mesp1 also promotes the expression of those genes whose products allow cell migration, and once the cardiogenic precursor cells are committed to become a heart, the cells migrate to the midline to form the heart tube (Lazic and Scott 2011).

Figure 1 Model gene regulatory network for the vertebrate heart initiated by BMP signals. BMP signaling activates the pivotal switches Nkx2-5 and Mesp1. These transcription factors act in concert to activate numerous heart-forming genes. Mesp1 has also been shown to repress genes that would otherwise specify the cell into other fates. The antagonism between Tbx20 (right side) and Tbx5 (left side) can also be seen. This model is provisional, as new ChIP-Seq techniques have identified thousands of promoters activated at different stages of heart development. (After May et al. 2012.)

 

Literature Cited

Andrée, B., D. Duprez, B. Vorbusch, H.-H. Arnold and T. Brand. 1998. BMP-2 induces ectopic expression of cardiac lineage markers and interferes with somite formation in chicken embryos. Mech. Dev. 70: 119–131.
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Bondue, A. and C. Blanpain. 2010. Mesp1: A key regulator of cardiovascular lineage commitment. Circ. Res. 107: 1414–1427.
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David, R. and 11 others. 2008. MesP1 drives vertebrate cardiovascular differentiation through Dkk-1-mediated blockade of Wnt-signalling. Nat. Cell Biol. 10: 338–345.
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Komuro, I. and S. Izumo. 1993. Csx: A murine homeobox-containing gene specifically expressed in the developing heart. Proc. Natl. Acad. Sci. USA 90: 8145–8149.
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Lints, T. J., L. M. Parsons, L. Hartley, I. Lyons and R. P. Harvey. 1993. Nkx2.5: A novel murine homeobox gene expressed in early heart progenitor cells and their myogenic descendants. Development 119: 419–431.
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May, D. and 16 others. 2012. Large-scale discovery of enhancers from human heart tissue. Nat. Genet. 44: 89–93.
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Pashmforoush, M. and 14 others. 2004. Nkx2-5 pathways and congenital heart disease: Loss of ventricular myocyte lineage specification leads to progressive cardiomyopathy and complete heart block. Cell 117: 373–386. 
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Prall, O. W. and 22 others. 2007. An Nkx2-5/Bmp2/Smad1 negative feedback loop controls heart progenitor specification and proliferation. Cell 128: 947–959.
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Schultheiss, T. M., S. Xydas and A. B. Lassar. 1995. Induction of avian cardiac myogenesis by anterior endoderm. Development 121: 4203–4214.
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Sugi, Y. and J. Lough. 1994. Anterior endoderm is a specific effector of terminal cardiac myocyte differentiation of cells from the embryonic heart forming region. Dev. Dyn. 200: 155–162.
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1. Mesp1 is a close relative of Mesp2, which directs somitogenesis (see Chapter 17). The tunicate has only one Mesp gene, and it specifies heart development through the activation of the Nkx and Hand genes, just as occurs in vertebrates (Satou et al. 2004). BMPs may activate Mesp1 indirectly by inducing the expression of Eomesodermin, a transcription factor that is important for both endoderm and mesodermal lineages. In the early mouse epiblast (which has low amounts of Nodal), Eomesodermin activates Mesp1. Later, as the primitive streak elongates, Eomesodermin acts with Nodal to activate genes for the Sox17 and Foxa2 transcription factors that specify the definitive endoderm (Costello et al. 2011).