GLI3 repressor controls functional development of the mouse ureter

Area of Science:

• Developmental Biology
• Molecular Biology
• Genetics

Background:

• Hydronephrosis and hydroureter are common antenatal abnormalities with poorly understood molecular causes.
• Hedgehog (Hh) signaling regulates tissue patterning and cell differentiation, involving GLI proteins.

Purpose of the Study:

• To investigate the role of Hh signaling in ureter morphogenesis and function.
• To identify molecular mechanisms underlying Hh-dependent ureter development and peristalsis.

Main Methods:

• Tissue-specific inactivation of Smoothened (Smo) in mouse models.
• Analysis of gene expression markers (Kit, Hcn3) and ureter function.
• Genetic manipulation of Gli3 in Smo-deficient embryos.

Main Results:

• Inactivation of Smo in the renal pelvis/upper ureter caused nonobstructive hydronephrosis and hydroureter with ureter dyskinesia.
• Reduced expression of Kit and Hcn3 was observed in mutant mice.
• Genetic inactivation of Gli3 rescued the observed abnormalities, restoring Kit and Hcn3 expression and ureter peristalsis.

Conclusions:

• Hh signaling is essential for coordinating ureter contractions by regulating Kit and Hcn3 expression.
• Dysregulation of Hh signaling and GLI3 repressor activity contributes to fetal hydronephrosis and hydroureter.