Mekk3 is essential for early embryonic cardiovascular development

  title={Mekk3 is essential for early embryonic cardiovascular development},
  author={Jianhua Yang and Melynda Boerm and Marya F. McCarty and Corazon D. Bucana and Isaiah J. Fidler and Yuan Yang and Bing Su},
  journal={Nature Genetics},
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 defined. We disrupted Map3k3 −/− (also known as Mekk3), which encodes Mekk3, a member of the Mekk/Ste11 family, in mice. Map3k3 −/− embryos died at approximately embryonic day (E) 11, displaying disruption of blood vessel development and… 

Erk5 null mice display multiple extraembryonic vascular and embryonic cardiovascular defects

The inability of Erk5-deficient mice to form a complex vasculature suggests thatErk5 may play an important role in controlling angiogenesis, and this data defines an essential role for ErK5 in cardiovascular development.

Knockout of ERK5 causes multiple defects in placental and embryonic development

ERK5 knockout mice die at approximately E10.5, and multiple developmental problems are seen in the ERK5-/- embryos, including an increase in apoptosis in the cephalic mesenchyme tissue, abnormalities in the hind gut, as well as problems in vascular remodelling, cardiac development and placental defects.

Targeted Deletion of mek5 Causes Early Embryonic Death and Defects in the Extracellular Signal-Regulated Kinase 5/Myocyte Enhancer Factor 2 Cell Survival Pathway

This is the first study to rigorously establish the role of MEK5 in vivo as an activator of ERK5 and as an essential regulator of cell survival that is required for normal embryonic development.

MEKK3 Initiates Transforming Growth Factor &bgr;2–Dependent Epithelial-to-Mesenchymal Transition During Endocardial Cushion Morphogenesis

The detection of MEKK3 transcripts to embryonic hearts before, during, and after cardiac cushion cells have executed epithelial-to-mesenchymal transition (EMT) is reported and suggest thatMEKK3 may function during production of cushion mesenchyme as required for valvular development and septation of the heart.

KLF2 Transcription Factor Modulates Blood Vessel Maturation through Smooth Muscle Cell Migration*

It is demonstrated that KLF2 is required for smooth muscle cell migration and elucidate a novel mechanism involving communication between PDGF and KLf2 in vascular maturation.

Requirement for Map2k1 (Mek1) in extra-embryonic ectoderm during placentogenesis

The essential role of Map2k1 in extra-embryonic ectoderm during placentogenesis is enlightened, as the Map2K1 gene function appears dispensable in the embryo and is rescued in tetraploid experiments.

MEKK3 is required for endothelium function but is not essential for tumor growth and angiogenesis.

Results suggest that MEKK3 plays a critical role in Ang1/Tie2 signaling to control endothelial cell proliferation and survival and is required for endothelial cells to interact with the myocardium during early embryonic development, however, MeKK3 is not essential for tumor growth and angiogenesis.

Mst1 and Mst2 Are Essential Regulators of Trophoblast Differentiation and Placenta Morphogenesis

It is suggested that Mst1/2 regulate placental development by control of trophoblast cell differentiation and labyrinthine vasculature at midgestation and Mst 1/2 control labyrinth morphogenesis in trophOBlast- and fetal endothelial-dependent manners.

Targeted deletion of BMK1/ERK5 in adult mice perturbs vascular integrity and leads to endothelial failure.

Direct genetic evidence is provided that the BMK1 pathway is critical for endothelial function and for maintaining blood vessel integrity and, surprisingly, mice lacking BMK 1 in cardiomyocytes developed to term without any apparent defects.



Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene

The unexpected finding that loss of a single VEGF allele is lethal in the mouse embryo between days 11 and 12 was reported, and angiogenesis and blood-island formation were impaired, resulting in several developmental anomalies.

Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice

The generation of mice deficient in Flk-1 by disruption of the gene using homologous recombination in embryonic stem (ES) cells is reported, indicating that FlK-1 is essential for yolk-sac blood-island formation and vasculogenesis in the mouse embryo.

Requirement of the MADS-box transcription factor MEF2C for vascular development.

Results reveal multiple roles for MEF2C in vascular development and suggest that MEF1-dependent target genes mediate endothelial cell organization and SMC differentiation and targeted deletion resulted in severe vascular abnormalities and lethality in homozygous mutants.

The transcription factor MEF2C-null mouse exhibits complex vascular malformations and reduced cardiac expression of angiopoietin 1 and VEGF.

Endocardiogenesis in the mutant was abnormal with the endothelial cells exhibiting a number of aberrant phenotypes, and a notable reduction in angiopoietin 1 and VEGF mRNA production by the myocardium, indicating that MEF2C is required for myocardial expression of these important endothelial-directed cytokines and thus for correct endocardial morphogenesis.

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

It is reported that formation of blood vessels was abnormal, but not abolished, in heterozygous VEGF-deficient (VEGF+/-) embryos, generated by aggregation of embryonic stem (ES) cells with tetraploid embryos (T-ES)16,17, and even more impaired in homozygous D1-VEGF- deficient (VDGF-/-) T-ES embryos, resulting in death at mid-gestation.

Dominant-negative and targeted null mutations in the endothelial receptor tyrosine kinase, tek, reveal a critical role in vasculogenesis of the embryo.

Observations demonstrate that the Tek signaling pathway plays a critical role in the differentiation, proliferation, and survival of endothelial cells in the mouse embryo.

Arteriovenous malformations in mice lacking activin receptor-like kinase-1

The early loss of anatomical, molecular and functional distinctions between arteries and veins indicates that Acvrl1 is required for developing distinct arterial and venous vascular beds.

Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium

It is reported that Flt-1 is essential for the organization of embryonic vasculature, but is not essential for endothelial cell differentiation, and it is suggested that the FlT-1 signalling pathway may regulate normal endothelium cell-cell or cell-matrix interactions during vascular development.

The receptor tyrosine kinase TIE is required for integrity and survival of vascular endothelial cells.

It is concluded that TIE is required during embryonic development for the integrity and survival of vascular endothelial cells, particularly in the regions undergoing angiogenic growth of capillaries.

Notch signaling is essential for vascular morphogenesis in mice.

An essential role for the Notch signaling pathway in regulating embryonic vascular morphogenesis and remodeling is revealed and it is indicated that whereas the NotCh4 gene is not essential during embryonic development, the notch4 and Notch1 genes have partially overlapping roles during embryogenesis in mice.