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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

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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 1

Smo deficiency targeted to the ureter mesenchyme results in nonobstructive hydroureter and hydronephrosis.

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Smo deficiency targeted to the ureter mesenchyme results in nonobstruct...
(A–F) Rarb2-Cre activity was notably absent from the cells surrounding the ureteric bud (arrow) at E11.5 (A and B), was weakly localized to the developing smooth muscle layer at E15.5 (C and D), and was strongly expressed in all mesenchyme-derived ureter cell layers of the proximal ureter at E18.5 (E and F). (G–J) E18.5 Rarb2-Cre;SmoloxP/– mutants exhibited hydroureter and hydronephrosis. Arrowheads in H denote dilated proximal ureter. (K and L) Nonobstructive hydroureter of Rarb2-Cre;SmoloxP/– mice, as demonstrated by intrapelvic dye injection. (M–R) Smo-deficient mutants did not exhibit ureter structural abnormalities, as indicated by hematoxylin and eosin staining (M and N), Masson trichrome stain for collagen-rich connective tissue layers (O and P), and normal expression of smooth muscle and specialized apical urothelium markers α-SMA and UpkIII, respectively (Q and R). u, urothelium; s, subepithelial stroma layer; m, smooth muscle layer; c, outer connective tissue layer. (S–V) Analysis of ureter peristalsis in isolated ureters revealed an absence of coordinated ureter contractions in the Rarb2-Cre;SmoloxP/– mutant (blue line [1], proximal ureter; red line [2], midproximal ureter; green line [3], mid-distal ureter; yellow line [4], distal ureter). In U and V, percent relaxation is plotted for the duration of a single peristaltic movement (x axis). (W and X) Kit-positive ICC-LCs (arrows) were absent in Rarb2-Cre;SmoloxP/– renal pelvis and proximal ureters. (Y and Z) Higher-magnification views of W and X. (AA and BB) Hcn3, a marker of a pelvic-kidney cell population required for ureter contraction initiation, was markedly reduced in Rarb2-Cre;SmoloxP/– mutants. Asterisks denote renal arterioles. Scale bars: 100 μm (A–F, M–T, and W–BB), 500 μm (G–L).
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