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Belief vs. scientific observation: The curious story of the precardiac mesoderm

The transition of primary nondifferentiated mesoderm to definitive cardiac tissue is a process that occurs within a relatively narrow developmental window (Eisenberg and Eisenberg, 2001). In the developing chick, this interval encompasses Hamburger-Hamilton (HH) (Hamburger and Hamilton, 1951) stages 4–8, which generally corresponds to 18–30 hr after egg laying. In a recent issue of Development, Redkar et al. (2001) describe a newly generated fate map that defines the location of the precardiac regions within the early chick embryo. The experimentation consisted of microinjecting the fluorescent label DiI into precisely localized regions within the mesodermal layer of early gastrula-stage embryos. After allowing the embryos to develop to tubular heart stages, the fates of individual labeled mesoderm cells were compiled, with regard to whether heart or nonheart tissue was subsequently labeled. The compiled cardiogenic fate map extends back as early as HH stage 4—the point during gastrulation where the primitive streak is fully elongated—thereby providing the first definitive fate map for this early stage. Moreover, by labeling embryos ranging from HH stages 4–8, Redkar et al. (2001) generated fate maps that describe the location of precardiac cells throughout gastrulation. Thus, by identifying the cells that will contribute to the primary heart tube, this comprehensive study provides information that is fundamental for understanding how the vertebrate heart emerges from nondifferentiated mesoderm. In many ways, the key period in the conversion of primary nondifferentiated mesoderm to heart tissue is HH stage 5. This is the time during chick development when the primitive streak begins to recede and the notochord begins to form. At HH stage 5, the precardiac or heartforming regions (HFRs) comprise two mesodermal fields within the anterior half of the embryo, which are bilaterally distributed with respect to the embryonic axis (Rawles, 1943; Rosenquist and DeHaan, 1966; Stalsberg and DeHaan, 1969). This point in heart development either coincides with or is just prior to the initial expression of several cardiac-associated transcription factors, such as Nkx2.5, SRF, Tbx-5, GATA4-6, and MEF2C (Croissant et al., 1996; Evans, 1997; Black and Olson, 1998; Evans, 1999; Yamada et al., 2000). The mesoderm at HH stage 5 is a simple cell layer. However, by HH stage 6, the lateral mesoderm begins to separate into two layers, with the precardiac cells continuing their residence within the splanchnic mesoderm (DeHaan, 1965). This rearrangement serves as a prelude to subsequent fusion of the two HFRs and, with this, the formation of the primary heart tube. As reported by Redkar et al. (2001), the medial border of the HFRs within the HH stage 5 embryo is located 0.3 mm lateral to the primitive groove. The anterior border of the HFRs resides just rostral to Hensen’s node, with the posterior border extending one-fourth of the distance down the primitive streak. One of the authors’ major conclusions from this new fate map is that “the putative cardiogenic marker Nkx2.5 does not govern the boundaries of the HFR as described in the literature.” The conclusion that the precardiac mesoderm doesn’t coincide with the Nkx2.5 expression domain may seem surprising. After all, this transcription factor has been singled out for its importance for promoting the cardiac phenotype. At HH stage 5, expression of the Nkx2.5 gene first appears in a crescent pattern that hugs the anterior-most edge of the embryo (Schultheiss et al., 1995). However, no one should be astonished by the newly generated fate map. Why not? Because, the location of the precardiac mesoderm within the HH stage 5 embryo was well documented 32 years earlier. In an amazingly well-executed radiolabeling study, Stalsberg and DeHaan (1969) reported a cardiogenic fate map that is almost identical to that reported by Redkar et al. (2001). Yet, it has been the misfortune of the cardiac developmental biology field that this earlier study—one of the true landmarks in this field—has been increasingly ignored. Its dismissal had little to do with the quality of the experimentation and all to do with its conclusions differing from the recent belief that formation of the vertebrate heart was the result of a simple pattern of gene expression—a theory that was readily accepted de-