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Renal agenesis and hypodysplasia in ret-k- mutant mice result from defects in ureteric bud development
A Schuchardt1, V D'Agati, V Pachnis
1Department of Genetics and Development, College of Physicians and Surgeons, Columbia University, NY 10032, USA.
Abstract:
The c-ret gene encodes a receptor tyrosine kinase that is expressed in the Wolffian duct and ureteric bud of the developing excretory system. Newborn mice homozygous for a mutation in c-ret displayed renal agenesis or severe hypodysplasia, suggesting a critical role for this gene in metanephric kidney development. To investigate the embryological basis of these defects, we characterized the early development of the excretory system in mutant homozygotes, and observed a range of defects in the formation, growth and branching of the ureteric bud, which account for the spectrum of renal defects seen at birth. Co-culture of isolated ureteric buds and metanephric mesenchyme show that the primary defect is intrinsic to the ureteric bud. While the mutant bud failed to respond to induction by wild-type mesenchyme, mutant mesenchyme was competent to induce the growth and branching of the wild-type bud. Furthermore, the mutant metanephric mesenchyme displayed a normal capacity to differentiate into nephric tubules when co-cultured with embryonic spinal cord. These findings suggest a model in which c-ret encodes the receptor for a (yet to be identified) factor produced by the metanephric mesenchyme, which mediates the inductive effects of this tissue upon the ureteric bud. This factor appears to stimulate the initial evagination of the ureteric bud from the Wolffian duct, as well as its subsequent growth and branching.
Insights
The c-ret gene is crucial for kidney development. Mutations cause defects in the ureteric bud, leading to kidney agenesis or hypodysplasia in newborn mice.
Area of Science:
- Developmental Biology
- Genetics
- Urology
Background:
- The c-ret gene encodes a receptor tyrosine kinase essential for excretory system development.
- Mutations in c-ret lead to renal agenesis or hypodysplasia, indicating its critical role in metanephric kidney formation.
Purpose of the Study:
- To investigate the embryological basis of renal defects caused by c-ret mutations.
- To elucidate the role of c-ret in ureteric bud and metanephric kidney development.
Main Methods:
- Characterization of early excretory system development in c-ret mutant mice.
- Co-culture experiments involving isolated ureteric buds and metanephric mesenchyme.
- Assessment of metanephric mesenchyme differentiation capacity.
Main Results:
- Mutant homozygotes exhibited defects in ureteric bud formation, growth, and branching, correlating with observed renal defects.
- The primary defect was intrinsic to the ureteric bud, which failed to respond to wild-type mesenchyme induction.
- Mutant mesenchyme retained the capacity to induce wild-type ureteric buds and differentiate into nephric tubules.
Conclusions:
- c-ret acts as a receptor for a mesenchyme-derived factor mediating ureteric bud induction.
- This c-ret-mediated signaling pathway is vital for ureteric bud evagination, growth, and branching during kidney development.