Dynamic signals linking the actin cytoskeleton and cell adhesion receptors are essential for morphogenesis during development and normal tissue homeostasis. Abi1 is a central regulator of actin polymerization and a binding partner of the Abl kinases. The α4 integrin receptor is associated with enhanced protrusive activity and regulation of directional cell migration. Among integrin subunits, α4 predominantly accumulates at the leading edge of migrating cells. We identified Abi1 as a crucial linker between α4 and the actin nucleation machinery at the leading edge. We generated Abi1 knockout mice and found that loss of Abi1 phenocopies knockout of α4. Mice lacking Abi1 or α4 exhibit mid-gestational lethality with abnormalities in placental and cardiovascular development. Abi1 null mice have reduced angiogenesis in the yolk sac, edema, and hemorrhage. Additionally, allantoic explants derived from Abi1 mutant mice exhibit impaired vascular plexus elaboration (Fig. 1).
Figure 1. Cardiovascular abnormalities in Abi1-/- embryos at E10.5. The yolk sac of the Abi1-/- embryo appears to have a diminished vasculature, with a reduction in the red blood cell content (B, compare to wild type in A). In C, the yolk sac has been dissected away, and the enlarged pericardial cavity with associated hemorrhage is apparent in the mutant (right). (D-F) Semi-thin plastic sections stained with toluidine blue show the enlarged pericardial cavity present in the Abi1 mutant (E). At higher magnification, disruption in the endocardium, epicardium, as well as myocardium can be appreciated in the mutant (G).
Further, Abi1 null mice have defective chorio-allantoic fusion. At the molecular level, purified Abi1 protein binds directly to the α4 cytoplasmic tail and endogenous Abi1 co-localizes with phosphorylated α4 at the leading edge of spreading cells. Abi1-deficient cells expressing α4 have impaired cell spreading, which is rescued by wild type Abi1 but not an Abi1 mutant lacking the α4-binding site. These data reveal the first direct link between the α4 integrin and actin polymerization and uncover a novel role for Abi1 in the regulation of morphogenesis in vivo (Ring et al., January 2011 PNAS cover image; vol. 108: 149-154).
