Calcineurin is required in urinary tract mesenchyme for the development of the pyeloureteral peristaltic machinery
Ching-Pin Chang, … , Gerald R. Crabtree, Feng Chen
Ching-Pin Chang, … , Gerald R. Crabtree, Feng Chen
Published April 1, 2004
Citation Information: J Clin Invest. 2004;113(7):1051-1058. https://doi.org/10.1172/JCI20049.
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Calcineurin is required in urinary tract mesenchyme for the development of the pyeloureteral peristaltic machinery

Abstract

Congenital obstructive nephropathy is the principal cause of renal failure in infants and children. The underlying molecular and cellular mechanisms of this disease, however, remain largely undetermined. We generated a mouse model of congenital obstructive nephropathy that resembles ureteropelvic junction obstruction in humans. In these mice, calcineurin function is removed by the selective deletion of Cnb1 in the mesenchyme of the developing urinary tract using the Cre/lox system. This deletion results in reduced proliferation in the smooth muscle cells and other mesenchymal cells in the developing urinary tract. Compromised cell proliferation causes abnormal development of the renal pelvis and ureter, leading to defective pyeloureteral peristalsis, progressive renal obstruction, and, eventually, fatal renal failure. Our study demonstrates that calcineurin is an essential signaling molecule in urinary tract development and is required for normal proliferation of the urinary tract mesenchymal cells in a cell-autonomous manner. These studies also emphasize the importance of functional obstruction, resulting from developmental abnormality, in causing congenital obstructive nephropathy.

Authors

Ching-Pin Chang, Bradley W. McDill, Joel R. Neilson, Heidi E. Joist, Jonathan A. Epstein, Gerald R. Crabtree, Feng Chen

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Pax3Cre directs Cnb1 deletion in the metanephric and the ureteric mesenc...
Pax3Cre directs Cnb1 deletion in the metanephric and the ureteric mesenchyme. (A) RT-PCR shows the expression of Cnb1 in the kidney and ureter of the mutant (Pax3CreT/+;Cnb1F/Δ) is reduced compared with that in the control (Pax3CreT/+;Cnb1F/+).GAPDH indicates equal loading. One hundred nanograms of total RNA was used in each lane. (B) Extensive Cre expression (revealed by lacZ expression; blue) was found in the kidney (K), ureter, and bladder (B) of the Pax3CreT/+;ROSAT/+ but not the Pax3Cre+/+;ROSAT/+ mice. (C–E and G) Samples from P1 Pax3CreT/+;ROSAT/+ mice. LacZ expression is evident in the glomeruli and tubules that are derived from the metanephric mesenchyme but not in the collecting duct system originated from the UB (C, ×20). The filled arrow in D points to the developing glomeruli. The open arrow points to one of the UB branches. In the developing renal pelvis, the SM layers (SM) and the adventitia (AD) express LacZ, while the UB-derived urothelium (UT) remains LacZ negative (D, ×40, and E, ×60). U, ureter; PP, papilla. The SM layers in the developing renal pelvic wall are illustrated by αSMA staining on a wild-type newborn sample (F, ×60). LacZ is also selectively expressed in the SM layers in the ureter but not in the urothelium (G, ×60). (H–K) Cnb1 protein can be detected by immunostaining in every cell in the control (H and J) but is absent in metanephric mesenchyme– and ureteric mesenchyme–derived structures in the mutant littermates (I and K). Cnb1 proteins remain in the UB-derived collecting duct (CD) system (open arrow) and the urothelium (filled arrow).