Vitamin A controls epithelial/mesenchymal interactions through Ret expression.

Area of Science:

• Developmental Biology
• Molecular Biology
• Genetics

Background:

• Mutations in the receptor tyrosine kinase RET gene cause Hirschsprung disease, cancer, and renal malformations.
• Kidney development relies on reciprocal signaling between ureteric bud epithelium and metanephric mesenchyme.
• Vitamin A deficiency is linked to embryonic abnormalities, including kidney malformations, mediated by retinoic acid receptors (RARs).

Purpose of the Study:

• To investigate the role of vitamin A signaling and RET in kidney development.
• To elucidate the interaction between stromal mesenchyme, ureteric bud, and RET signaling.
• To determine if RET signaling can rescue renal defects caused by vitamin A pathway disruption.

Main Methods:

• Generated and analyzed mice deficient for Rara and Rarb2 genes (Rara(-/-)Rarb2(-/-)).
• Utilized genetic rescue by forcing expression of Ret in Rara(-/-)Rarb2(-/-) mice.
• Observed and compared renal development, ureteric bud growth, and stromal cell patterning in wild-type and mutant mice.

Main Results:

• Deletion of Rara and Rarb2 in stromal mesenchyme led to altered stromal patterning and impaired ureteric bud growth with reduced Ret expression.
• Forced expression of Ret in Rara(-/-)Rarb2(-/-) mice genetically rescued renal development, restoring ureteric bud growth and stromal cell patterning.
• Identified a novel reciprocal signaling loop: vitamin A-dependent stromal signals control ureteric bud Ret expression, and Ret-dependent ureteric bud signals control stromal patterning.

Conclusions:

• A novel reciprocal signaling loop exists between ureteric bud epithelium and stromal mesenchyme, dependent on RET and vitamin A.
• Vitamin A signaling in stromal cells is essential for regulating RET expression in the ureteric bud.
• RET signaling in the ureteric bud is critical for proper stromal cell patterning during kidney development.