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Mekk3 is essential for early embryonic cardiovascular development

Abstract

The early development of blood vessels consists of two phases, vasculogenesis and angiogenesis, which involve distinct and also overlapping molecular regulators, but the intracellular signal transduction pathways involved in these processes have not been well defined1,2,3,4. We disrupted Map3k3 −/− (also known as Mekk3), which encodes Mekk3, a member of the Mekk/Ste11 family5,6, in mice. Map3k3 −/− embryos died at approximately embryonic day (E) 11, displaying disruption of blood vessel development and the structural integrity of the yolk sac. Angiogenesis was blocked at approximately E9.5 in mutant embryos. Map3k3 disruption did not alter the expression of the genes encoding Vegf-1, angiopoietin or their receptors. The development of embryonic, but not maternal, blood vessels in the placentas of Map3k3 −/− embryos was impaired, revealing an intrinsic defect in Map3k3−/− endothelial cells. Moreover, Mekk3 activated myocyte-specific enhancer factor 2C (Mef2c), a transcription factor crucial for early embryonic cardiovascular development through the p38 mitogen-activated protein kinase (Mapk) cascade. We conclude that Mekk3 is necessary for blood vessel development and may be a possible target for drugs that control angiogenesis.

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Figure 1: Map3k3 targeting vector and analysis of targeted mutation of Map3k3.
Figure 2: RT–PCR analysis of gene expression in E9 wild-type (WT) and Map3k3−/− yolk sacs and embryos.
Figure 3: Comparison of the phenotypes of wild-type and Map3k3−/− embryos.
Figure 4: Map3k3 mutation caused defects in blood vessel development in heart, brain and intersomitic regions.
Figure 5: Mekk3 activated Mef2c transcriptional activity through the p38 Mapk pathway.

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Acknowledgements

We thank M. Karin for encouragement and support throughout the project; M. Karin and J. Han for expression vectors; R. Behringer for critically reading the manuscript; L. Gan, W. Shou, E. Li, R. Johnson, H. Chen and D. Reynods for advice and technical help on the mouse embryonic studies; T. Sato for the whole-mount staining protocol; and M. Goode and W. Pagel for editing the manuscript. These studies were partially supported by a grant from the American Cancer Society (RPG –97-090) to B.S.

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Correspondence to Bing Su.

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Yang, J., Boerm, M., McCarty, M. et al. Mekk3 is essential for early embryonic cardiovascular development. Nat Genet 24, 309–313 (2000). https://doi.org/10.1038/73550

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