GLI3 repressor controls functional development of the mouse ureter
Jason E. Cain, … , Joshua Blake, Norman D. Rosenblum
Jason E. Cain, … , Joshua Blake, Norman D. Rosenblum
Published February 21, 2011
Citation Information: J Clin Invest. 2011;121(3):1199-1206. https://doi.org/10.1172/JCI45523.
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Research Article

GLI3 repressor controls functional development of the mouse ureter

Abstract

Obstructive and nonobstructive forms of hydronephrosis (increased diameter of the renal pelvis and calyces) and hydroureter (dilatation of the ureter) are the most frequently detected antenatal abnormalities, yet the underlying molecular mechanisms are largely undefined. Hedgehog (Hh) proteins control tissue patterning and cell differentiation by promoting GLI-dependent transcriptional activation and by inhibiting the processing of GLI3 to a transcriptional repressor. Genetic mutations that generate a truncated GLI3 protein similar in size to the repressor in humans with Pallister-Hall syndrome (PHS; a disorder whose characteristics include renal abnormalities) and hydroureter implicate Hh-dependent signaling in ureter morphogenesis and function. Here, we determined that Hh signaling controls 2 cell populations required for the initiation and transmission of coordinated ureter contractions. Tissue-specific inactivation of the Hh cell surface effector Smoothened (Smo) in the renal pelvic and upper ureteric mesenchyme resulted in nonobstructive hydronephrosis and hydroureter characterized by ureter dyskinesia. Mutant mice had reduced expression of markers of cell populations implicated in the coordination of unidirectional ureter peristalsis (specifically, Kit and hyperpolarization-activation cation–3 channel [Hcn3]), but exhibited normal epithelial and smooth muscle cell differentiation. Kit deficiency in a mouse model of PHS suggested a pathogenic role for GLI3 repressor in Smo-deficient embryos; indeed, genetic inactivation of Gli3 in Smo-deficient mice rescued their hydronephrosis, hydroureter, Kit and Hcn3 expression, and ureter peristalsis. Together, these data demonstrate that Hh signaling controls Kit and Hcn3 expression and ureter peristalsis.

Authors

Jason E. Cain, Epshita Islam, Fiona Haxho, Joshua Blake, Norman D. Rosenblum

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Figure 3

Elimination of GLI3 repressor in the Smo-deficient background rescues the renal phenotype.

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Elimination of GLI3 repressor in the Smo-deficient background rescues th...
(A–G) Analysis of Rarb2-Cre;SmoloxP/–;Gli3XtJ/XtJ embryos at E18.5 revealed normalization of kidney and ureter morphology (A–C), rescue of coordinated proximal-distal ureter contractions (D and E; blue line [1], proximal ureter; red line [2], midproximal ureter; green line [3], mid-distal ureter; yellow line [4], distal ureter), and restoration of Kit (F) and Hcn3 (G) expression. In E, percent relaxation is plotted for the duration of a single peristaltic movement (x axis). Scale bars: 100 μm (D, F, and G), 500 μm (A–C). (H) Model for a bifunctional role for Hh signaling during the functional development of the ureter. (i) Shh secreted by the ureteric bud/urothelium is required during early development for smooth muscle cell development and the patterning of the ureter mesenchyme. (ii) During later development, SHH-SMO dependent signaling is required for Kit and Hcn3 expression in distinct cell populations that regulate coordinated ureter contractions. SHH signaling to adjacent cells promotes pathway activation and prevents formation of GLI3 repressor (GLI3R). In the presence of GLI3 repressor function during ureter morphogenesis, smooth muscle cell differentiation and expression of Kit and Hcn3 is impaired, leading to abnormal ureter function. u, ureteric bud/urothelium; um, ureter mesenchyme; s, subepithelial layer; sm, smooth muscle; c, outer connective tissue.