Yap and Taz are required for Ret-dependent urinary tract morphogenesis

Area of Science:

• Developmental Biology
• Molecular Biology
• Urology

Background:

• Congenital lower urinary tract abnormalities are common but poorly understood at the molecular and cellular levels.
• The Hippo pathway, involving Yap and Taz, is crucial for organ development.

Purpose of the Study:

• To investigate the roles of Yap and Taz in the development of the nephric duct (ND) and lower urinary tract.
• To elucidate the molecular mechanisms underlying congenital lower urinary tract defects.

Main Methods:

• Conditional knockout of Yap and Taz in the nephric duct lineage using a genetic approach.
• Analysis of kidney and ureter morphology, ND-cloaca interaction, and gene expression.
• Investigating the interaction between Yap/Taz and RET signaling pathways.

Main Results:

• Yap deletion in the ND leads to hydronephrosis and megaureters due to aberrant ND-cloaca connection and detachment.
• Taz deletion alone has no effect, but Yap and Taz show partially redundant roles in ureterovesical junction formation.
• Yap deficiency enhances RET signaling, evidenced by increased budding, phospho-ERK, and specific gene expression, which can be rescued by reducing Ret gene dosage.

Conclusions:

• Yap/Taz activity is essential for proper nephric duct development and ureterovesical junction formation.
• Disruption of Yap/Taz enhances RET pathway activity, contributing to the pathogenesis of lower urinary tract defects.
• Findings provide insights into molecular mechanisms of congenital urinary tract abnormalities and potential therapeutic targets.