RESUMO
Myc-deficient mice fail to develop normal vascular networks and Myc-deficient embryonic stem cells fail to provoke a tumor angiogenic response when injected into immune compromised mice. However, the molecular underpinnings of these defects are poorly understood. To assess whether Myc indeed contributes to embryonic vasculogenesis we evaluated Myc function in Xenopus laevis embryogenesis. Here, we report that Xc-Myc is required for the normal assembly of endothelial cells into patent vessels during both angiogenesis and lymphangiogenesis. Accordingly, the specific knockdown of Xc-Myc provokes massive embryonic edema and hemorrhage. Conversely, Xc-Myc overexpression triggers the formation of ectopic vascular beds in embryos. Myc is required for normal expression of Slug/Snail2 and Twist, and either XSlug/Snail2 or XTwist could compensate for defects manifest by Xc-Myc knockdown. Importantly, knockdown of Xc-Myc, XSlug/Snail2 or XTwist within the lateral plate mesoderm, but not the neural crest, provoked embryonic edema and hemorrhage. Collectively, these findings support a model in which Myc, Twist and Slug/Snail2 function in a regulatory circuit within lateral plate mesoderm that directs normal vessel formation in both the vascular and lymphatic systems.
Assuntos
Neovascularização Fisiológica/fisiologia , Proteínas Proto-Oncogênicas c-myc/fisiologia , Proteína 1 Relacionada a Twist/fisiologia , Proteínas de Xenopus/fisiologia , Xenopus laevis/fisiologia , Animais , Western Blotting , Embrião não Mamífero/irrigação sanguínea , Embrião não Mamífero/embriologia , Embrião não Mamífero/metabolismo , Deleção de Genes , Regulação da Expressão Gênica no Desenvolvimento , Hibridização In Situ , Linfangiogênese/genética , Linfangiogênese/fisiologia , Neovascularização Fisiológica/genética , Crista Neural/embriologia , Crista Neural/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteína 1 Relacionada a Twist/genética , Proteína 1 Relacionada a Twist/metabolismo , Proteínas de Xenopus/genética , Proteínas de Xenopus/metabolismo , Xenopus laevis/genética , Xenopus laevis/metabolismoRESUMO
c-Myc promotes cell growth and transformation by ill-defined mechanisms. c-myc(-/-) mice die by embryonic day 10.5 (E10.5) with defects in growth and in cardiac and neural development. Here we report that the lethality of c-myc(-/-) embryos is also associated with profound defects in vasculogenesis and primitive erythropoiesis. Furthermore, c-myc(-/-) embryonic stem (ES) and yolk sac cells are compromised in their differentiative and growth potential. These defects are intrinsic to c-Myc, and are in part associated with a requirement for c-Myc for the expression of vascular endothelial growth factor (VEGF), as VEGF can partially rescue these defects. However, c-Myc is also required for the proper expression of other angiogenic factors in ES and yolk sac cells, including angiopoietin-2, and the angiogenic inhibitors thrombospondin-1 and angiopoietin-1. Finally, c-myc(-/-) ES cells are dramatically impaired in their ability to form tumors in immune-compromised mice, and the small tumors that sometimes develop are poorly vascularized. Therefore, c-Myc function is also necessary for the angiogenic switch that is indispensable for the progression and metastasis of tumors. These findings support the model wherein c-Myc promotes cell growth and transformation, as well as vascular and hematopoietic development, by functioning as a master regulator of angiogenic factors.