Essential role for p38α mitogen-activated protein kinase in placental angiogenesis

Abstract

The p38 family of mitogen-activated protein kinases (MAPKs) mediates signaling in response to environmental stresses and inflammatory cytokines, but the requirements for the p38 MAPK pathway in normal mammalian development have not been elucidated. Here, we show that targeted disruption of the p38␣ MAPK gene results in homozygous embryonic lethality because of severe defects in placental development. Although chorioallantoic placentation is initiated appropriately in p38␣ null homozygotes, placental defects are manifest at 10.5 days postcoitum as nearly complete loss of the labyrinth layer and significant reduction of the spongiotrophoblast. In particular, p38␣ mutant placentas display lack of vascularization of the labyrinth layer as well as increased rates of apoptosis, consistent with a defect in placental angiogenesis. Furthermore, p38␣ mutants display abnormal angiogenesis in the embryo proper as well as in the visceral yolk sac. Thus, our results indicate a requirement for p38␣ MAPK in diploid trophoblast development and placental vascularization and suggest a more general role for p38 MAPK signaling in embryonic angiogenesis.

MAPK signaling in inflammation-associated cancer development

“…Loss of p38 causes embryonic lethality between embryonic day 10.5 and 16.5 in mice. Impaired vascularization of the placenta was proposed as the cause of death (Adams et al, 2000;Allen et al, 2000;Mudgett et al, 2000;Tamura et al, 2000). Mice with disruption of other p38 isoforms are viable and fertile.…”

MAP3Ks as central regulators of cell fate during development

“…Furthermore, increased p38 levels have been shown to inhibit TAK1 activity, suggesting that a negative feedback mechanism contributes to the regulation of the TAK1/p38 pathway (Cheung et al, 2003). Similar to TAK1-deficient mice, MAPK p38␣ knockout mice also exhibit abnormalities in vascular development, although yolk sac angiogenesis does not appear to be affected in the latter (Adams et al, 2000;Mudgett et al, 2000). These differences in phenotype between the TAK1 and p38␣ null mice may be due to redundant activity of other p38 isoforms in the yolk sac which may compensate for the lack of p38␣ in this tissue (Ihle, 2000).…”

MKK signaling and vascularization

“…Knockout of p38alpha MAPK causes embryonic lethality starting at E10.5 that is characterized by cardiovascular defects in the embryo that arise secondarily to defects in placental vascularization (Adams et al, 2000;Mudgett et al, 2000) and defective hematopoeisis (Tamura et al, 2000). By contrast, p38beta MAPK knockouts are viable and apparently healthy.…”