Dual roles for the Dab2 adaptor protein in embryonic development and kidney transport.
The Disabled-2 (Dab2) gene has been proposed to act as a tumor suppressor. Cell culture studies have implicated Dab2 in signal transduction by mitogens, TGFbeta and endocytosis of lipoprotein receptors. To identify in vivo functions of Dab2, targeted mutations were made in the mouse. In the absence of Dab2, embryos arrest prior to gastrulation with a phenotype reminiscent of those caused by deletion of some TGFbeta signal transduction molecules involved in Nodal signaling. Dab2 is expressed in the extra-embryonic visceral endoderm but not in the epiblast. Dab2 could be conditionally deleted from the embryo without affecting normal development, showing that Dab2 is required in the visceral endoderm but dispensable in the embryo proper. Conditionally mutant Dab2(-/-) mice are overtly normal, but have reduced clathrin-coated pits in kidney proximal tubule cells and excrete specific plasma proteins in the urine, consistent with reduced transport by a lipoprotein receptor, megalin/gp330, in the proximal tubule. This evidence indicates that Dab2 is pleiotropic and regulates both visceral endoderm function and lipoprotein receptor trafficking in vivo.
Morris
Shelli M
SM
Fred Hutchinson Cancer Research Center, Division of Basic Sciences, 1100 Fairview Avenue North, Seattle, WA 98109, USA.
Tallquist
Michelle D
MD
Rock
Charles O
CO
Cooper
Jonathan A
JA
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D001692:Biological Transport; D047108:Embryonic Development; D005314:Embryonic and Fetal Development; D004707:Endoderm / Q000378:metabolism; D005260:Female; D018390:Gene Targeting; D016147:Genes, Tumor Suppressor; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000378:metabolism / Q000473:pathology; D051379:Mice; D011247:Pregnancy; D011270:Pregnancy, Animal; D011506:Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D012177:Retinol-Binding Proteins / Q000378:metabolism; D054839:Retinol-Binding Proteins, Plasma; D025521:Tumor Suppressor Proteins; D014809:Vitamin D-Binding Protein / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D051017:Apoptosis Regulatory Proteins; C102885:DAB2 protein, human; D011506:Proteins; D012177:Retinol-Binding Proteins; D054839:Retinol-Binding Proteins, Plasma; D025521:Tumor Suppressor Proteins; D014809:Vitamin D-Binding Protein