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Role of platelet-derived growth factors in mouse development
1Department of Medical Biochemistry, University of Göteborg, Sweden.
Abstract:
The current understanding of platelet-derived growth factor (PDGF) physiological functions in vivo is discussed in the context of mouse development. In particular, the review focuses on recent experiments in which genetic approaches have been applied in order to mutate the PDGF and PDGF receptor genes in the mouse. Thus, the PDGF-B and PDGF beta receptor (PDGFRb) genes were recently inactivated by homologous recombination in embryonic stem cells. Their phenotypes are highly similar, displaying cardiovascular, hematological and renal defects. The latter is particularly interesting since it consists of a specific cellular defect: the complete loss of kidnety glomerular mesangial cells. As such, the phenotype not only sheds light on the developmental importance of PDGF-B-PDGFRb interactions, but also reveals information about the function of mesangial cells. Based on detailed morphological studies of mutant glomeruli and the absence of urine collection in the urinary bladder, I propose that the mesangial cells function as interior "filter holders", the "filter" consisting of the glomerular basement membrane and associated cell types. The filter holder model would predict that glomerular filtration is critically dependent on an interior structural support of the filter, which is normally provided by the mesangial cells and the mesangial matrix. In addition to the mutants generated by gene targeting, the mouse patch mutation is discussed. This deletion encompasses the PDGFRa locus. The last part of the review focuses on the problems encountered when interpreting gene knockout phenotypes in the physiological functions of gene products.
Insights
Platelet-derived growth factor (PDGF) is crucial for mouse development, particularly for kidney mesangial cells. Genetic mutations in PDGF-B and PDGF beta receptor (PDGFRb) reveal mesangial cells act as "filter holders" supporting kidney filtration.
Area of Science:
- Developmental Biology
- Genetics
- Nephrology
Background:
- Platelet-derived growth factor (PDGF) plays vital roles in physiological functions.
- Understanding PDGF's in vivo functions requires studying its developmental impact.
Purpose of the Study:
- To investigate the physiological functions of PDGF and its receptors during mouse development.
- To elucidate the role of PDGF-B and PDGFRb in kidney development and mesangial cell function.
Main Methods:
- Gene targeting via homologous recombination in embryonic stem cells to inactivate PDGF-B and PDGFRb genes.
- Analysis of resulting mouse phenotypes, focusing on cardiovascular, hematological, and renal defects.
- Morphological studies of mutant glomeruli and examination of urinary system function.
Main Results:
- Inactivation of PDGF-B and PDGFRb genes resulted in similar phenotypes, including cardiovascular, hematological, and renal defects.
- A specific defect observed was the complete loss of kidney glomerular mesangial cells.
- The study proposes a "filter holder" model where mesangial cells provide structural support for glomerular filtration.
Conclusions:
- PDGF-B and PDGFRb signaling is essential for the development and survival of glomerular mesangial cells.
- Mesangial cells are critical for maintaining the structural integrity of the glomerular filtration barrier.
- The study highlights the challenges in interpreting gene knockout phenotypes in relation to physiological functions.