Abstract
BackgroundDisabled-2 (Dab2) is an endocytic adaptor protein involved in clathrin-mediated endocytosis and cargo trafficking. Since its expression is lost in several cancer types, Dab2 has been suggested to be a tumor suppressor. In vitro studies indicate that Dab2 establishes epithelial cell polarity and organization by directing endocytic trafficking of membrane glycoproteins. Dab2 also modulates cellular signaling pathways by mediating the endocytosis and recycling of surface receptors and associated signaling components. Previously, two independent gene knockout studies have been reported, with some discrepancies in the observed embryonic phenotypes. To further clarify the in vivo roles of Dab2 in development and physiology, we designed a new floxed allele to delete dab2 gene.ResultsThe constitutive dab2 deleted embryos showed a spectrum in the degree of endoderm disorganization in E5.5 and no mutant embryos persisted at E9.5. However, the mice were grossly normal when dab2 deletion was restricted to the embryo proper and the gene was retained in extraembryonic tissues using Meox2-Cre and Sox2-Cre. Adult Dab2-deficient mice had a small but statistically significant increase in serum cholesterol levels.ConclusionThe study of the new dab2 mutant allele in embryos and embryoid bodies confirms a role for Dab2 in extraembryonic endoderm development and epithelial organization. Experimental results with embryoid bodies suggest that additional endocytic adaptors such as Arh and Numb could partially compensate for Dab2 loss. Conditional deletion indicates that Dab2 is dispensable for organ development, when the vast majority of the embryonic cells are dab2 null. However, Dab2 has a physiological role in the endocytosis of lipoproteins and cholesterol metabolism.
Highlights
Disabled-2 (Dab2) is an endocytic adaptor protein involved in clathrin-mediated endocytosis and cargo trafficking
The polarized trafficking of cell adhesion molecules such as integrins and E-cadherin may explain the role of Dab2 in epithelial polarity and organization [18] and trafficking of signaling surface receptors may account for its activity in modulating multiple signaling pathways [5,28,37]
Consistent with our prior conclusion [18,19], the current analysis of both embryos and embryoid bodies indicates that loss of Dab2 leads to disorganization of primitive endoderm and subsequent extraembryonic endoderm, the differentiation to endoderm lineage is not impaired
Summary
Disabled-2 (Dab2) is an endocytic adaptor protein involved in clathrin-mediated endocytosis and cargo trafficking. Dab mediates the simultaneous attachment of clathrin-coated cargos containing transmembrane proteins with one or more NPXY motifs, such as the low density lipoprotein (LDL) receptor, megalin, and integrins, to the myosin motor, enabling endocytosis and directional trafficking. Modulation of LDL receptor endocytosis by Dab has been studied in cultured cells [36], though a role in vivo has not yet been established. The polarized trafficking of cell adhesion molecules such as integrins and E-cadherin may explain the role of Dab in epithelial polarity and organization [18] and trafficking of signaling surface receptors may account for its activity in modulating multiple signaling pathways [5,28,37]
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