Mesp1 Expression Is the Earliest Sign of Cardiovascular Development

doi:10.1016/S1050-1738(01)00069-X

Trends in Cardiovascular Medicine

Volume 10, Issue 8, November 2000, Pages 345-352

https://doi.org/10.1016/S1050-1738(01)00069-X Get rights and content

Abstract

Understanding the molecular mechanism leading to formation of the heart and vasculature during embryogenesis is critically important because malformation of the cardiovascular system is the most frequently occurring type of birth defect. While the hearts of all vertebrates are derived from bilateral paired fields of primary mesodermal cells that are specified to the cardiac lineage during gastrulation, the mechanism for lineage restriction, and the origin of the myocardium and endocardium have not been defined. Recently, we found that a transcription factor, Mesp1, is expressed in almost all precursors of the cardiovascular system and plays an essential role in cardiac morphogenesis. Mesp1 may play a key role in the early specification for cardiac precursor cells.

Section snippets

Mesp1 Is Expressed in the Early Mesoderm and Involved in Cardiac Morphogenesis

Mesp1, belonging to the bHLH transcription factor family, is expressed in the early mesoderm at the onset of gastrulation (Figure 1 and Saga et al. 1996). The expression of the transcript is restricted to a part of mesoderm ingressed through the primitive streak of the early stage embryo (6.5–7.0 dpc) and quickly down-regulated after 7.5 dpc and no expression has been observed in the paraxial or axial mesoderm. Only the slight expression observed at a later stage embryo (8.5 dpc in Figure 1)

Mesp1-Expressing Cell Lineage

Cell type-specific genomic alternations mediated by the (Figure 2) Cre/loxP system constitute a powerful approach to the study of cell lineages Trainor et al. 1999, Yamauchi et al. 1999, Zinyk et al. 1998. On crossing heterozygous Mesp1-Cre and reporter mice CAG-CAT-Z, one quarter of the progeny should consist of double transgenics (Figure 2A). Only cells that express Cre from the Mesp1 allele should undergo recombination between the loxP sites of the reporter construct, excising the CAT gene

Mesp1, Mesp2 Double Knockout Mouse

The abnormal heart morphogenesis in Mesp1 (−/−) embryos resulting in cardia bifida is caused by delayed migration of the cardiac precursor cells. However, the initial suppression of cell migration is rescued at the later stages and the Mesp1 (−/−) embryo eventually generates an abnormal heart tube. The involvement of Mesp2, another gene of the same family, is indicated because of the similar expression pattern. An early expression study did not reveal Mesp2 expression at the early stage embryo,

Chimera Analysis Reveals Cell-autonomous Function of Mesp1 and Mesp2 in Cardiac Morphogenesis

Mesp1 and Mesp2 are expressed only in the early ingressed group of mesoderm and not in the paraxial and axial mesoderm. No paraxial mesoderm was generated in the dKO embryo, which resulted in a complete lack of somites. To clarify whether such mesodermal defects observed in the Mesp1,p2-dKO embryo are of a cell-autonomous or non-cell-autonomous consequence, chimera analysis was conducted (see Figure 4 for the method). A chimeric embryo was generated by aggregating 8-cell embryos derived from

Discussion

Mesodermal cells generate the heart tube. The embryonic mesoderm can be divided into five regions; the chorda (axial) mesoderm, somitic dorsal (paraxial) mesoderm, intermediate mesoderm, lateral plate mesoderm, and head mesenchyme (Gilbert 2000). It is generally thought that the heart is derived from the lateral plate mesoderm. The results of our experiments and fate mapping studies (Tam et al. 2000) showed that the heart precursors in mouse are clearly localized as the cranial-cardiac mesoderm

Conclusion

The series of experiments described here involving cell lineage, loss of function and chimeric analyses revealed a differential requirement of Mesp1 and Mesp2 for different cell lineages. For the extraembryonic mesoderm, lack of Mesp1 and Mesp2 did not result in a severe defect in either mesodermal formation or subsequent cell differentiation, suggesting that these genes may not be required for extraembryonic mesoderm development or, alternatively, other molecules may rescue the deficiency of

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Brief reviewsMesp1 Expression Is the Earliest Sign of Cardiovascular Development

Abstract

Section snippets

Mesp1 Is Expressed in the Early Mesoderm and Involved in Cardiac Morphogenesis

Mesp1-Expressing Cell Lineage

Mesp1, Mesp2 Double Knockout Mouse

Chimera Analysis Reveals Cell-autonomous Function of Mesp1 and Mesp2 in Cardiac Morphogenesis

Discussion

Conclusion

Dev Biol

Dev Biol

Dev Biol

Dev Biol

Biochem Biophys Res Commun

Dev Biol

Serum response factor is essential for mesoderm formation during mouse embryogenesis

EMBO J

Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele

Nature

Smad5 knockout mice die at mid-gestation due to multiple embryonic and extraembryonic defects

Development

VEGF mediates angioblast migration during development of the dorsal aorta in Xenopus

Development

Tissue-specific requirements for the proprotein convertase Furin/SPC1 during embryonic turning and heart looping

Development

Molecular regulation of atrioventricular valvuloseptal morphogenesis

Circ Res

Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene

Nature

Fashioning the vertebrate heartearliest embryonic decisions

Development

Defects in mesoderm, neural tube and vascular development in mouse embryos lacking fibronectin

Development

Role of neurla crest in congenital heart disease

Circulation

Mesp1 and Mesp2 are essential for the development of cardiac mesoderm

Development

Brief reviews
Mesp1 Expression Is the Earliest Sign of Cardiovascular Development