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Dual roles for the Dab2 adaptor protein in embryonic development and kidney transport
Shelli M Morris1, Michelle D Tallquist, Charles O Rock
1Fred Hutchinson Cancer Research Center, Division of Basic Sciences, 1100 Fairview Avenue North, Seattle, WA 98109, USA.
Abstract:
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.
Insights
The Disabled-2 (Dab2) gene is crucial for early embryonic development and visceral endoderm function. In vivo, Dab2 also regulates lipoprotein receptor trafficking in kidney cells.
Area of Science:
- Molecular Biology
- Developmental Biology
- Genetics
Background:
- The Disabled-2 (Dab2) gene is implicated as a tumor suppressor.
- Cell culture studies suggest Dab2's role in mitogen signaling, TGF-beta pathways, and lipoprotein receptor endocytosis.
Purpose of the Study:
- To elucidate the in vivo functions of the Dab2 gene.
- Investigate Dab2's role in early embryonic development and adult kidney function.
Main Methods:
- Generation of targeted mutations in the mouse model to study Dab2 function.
- Utilizing conditional gene deletion to assess Dab2's requirement in specific tissues (visceral endoderm vs. embryo proper).
- Phenotypic analysis of Dab2-deficient embryos and adult mice, including examination of kidney proximal tubule cells and urinary protein excretion.
Main Results:
- Absence of Dab2 leads to embryonic arrest prior to gastrulation, similar to defects in Nodal signaling.
- Dab2 is essential in the visceral endoderm but dispensable in the epiblast for embryonic development.
- Dab2-deficient mice exhibit normal overall development but show reduced clathrin-coated pits in kidney proximal tubules.
- These mice excrete plasma proteins in urine, indicating impaired lipoprotein receptor (megalin/gp330) trafficking.
Conclusions:
- Dab2 is a pleiotropic gene with critical roles in both early embryonic development (visceral endoderm function) and adult physiology (lipoprotein receptor trafficking).
- The findings highlight Dab2's importance in maintaining kidney function through receptor-mediated transport.