International Mammalian Genome Society

logo18th International Mouse Genome Conference

17-22 October 2004, Seattle, USA


Chen M 2, Asakura M 1, Nakamura T 1, Inoue H 1, Schneider M 1

1 Baylor College of Medicine, Houston, United States, 2 Agilent Technologies, Palo Alto, United States

Early steps for cardiac lineage specification are problematic to study in mammalian embryos, which has favored the use of pluripotent cells that recapitulate the onset of cardiac myogenesis.

In mouse P19 cells or their derivatives, it has been shown that bone morphogenetic proteins drive Nkx2.5 induction both via receptor-activated Smad transcription factors and by TGF beta-activated kinase-1 (MAP3K7), and that Wnts (a reported inhibitor of heart formation in avian or amphibian explants) can activate cardiogenesis both via a non-canonical pathway for Wnt11 and via the canonical beta-catenin pathway, acting prior to and upstream of the endogenous BMPs’ induction.

Here, we have undertaken a dissection of the BMP- and Wnt-dependent pathways in P19Cl6 cells, by DNA microarray expression profiling in the absence or presence of extracellular inhibitors.

Blocking Wnt signaling with soluble Frizzled protein (sFz-8/Fc) and BMP signaling with noggin inhibited the induction of sarcomeric myosin heavy chains, suggesting that sFz-8/Fc and noggin inhibited cardiac differentiation in these cells.  Blocking Wnt signaling with sFz-8/Fc revealed that many reported cardiogenic or mesoderm-inducing genes were Wnt-dependent in this system, including the growth factors Cripto and FGF-8 and the transcription factors brachyury/T and eomesodermin.  Interestingly, blocking BMPs with noggin also prevented the early induction of T, eomesodermin, Cripto, and FGF-8, along with Wnts 3 and 5a and the Wnt receptors.

Thus: (1) Reciprocating Wnt- and BMP-dependent pathways promote cardiogenesis in this model system. (2) Cripto and FGF-8 are inducted by dual Wnt- and BMP-dependent circuits.

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