Tbx18 regulates the development of the ureteral mesenchyme
Rannar Airik, … , Marianne Petry, Andreas Kispert
Rannar Airik, … , Marianne Petry, Andreas Kispert
Published March 1, 2006
Citation Information: J Clin Invest. 2006;116(3):663-674. https://doi.org/10.1172/JCI26027.
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Research Article Nephrology

Tbx18 regulates the development of the ureteral mesenchyme

Abstract

Congenital malformations of the urinary tract are a major cause of renal failure in children and young adults. They are often caused by physical obstruction or by functional impairment of the peristaltic machinery of the ureter. The underlying molecular and cellular defects are, however, poorly understood. Here we present the phenotypic characterization of a new mouse model for congenital ureter malformation that revealed the molecular pathway important for the formation of the functional mesenchymal coating of the ureter. The gene encoding the T-box transcription factor Tbx18 was expressed in undifferentiated mesenchymal cells surrounding the distal ureter stalk. In Tbx18–/– mice, prospective ureteral mesenchymal cells largely dislocalized to the surface of the kidneys. The remaining ureteral mesenchymal cells showed reduced proliferation and failed to differentiate into smooth muscles, but instead became fibrous and ligamentous tissue. Absence of ureteral smooth muscles resulted in a short hydroureter and hydronephrosis at birth. Our analysis also showed that the ureteral mesenchyme derives from a distinct cell population that is separated early in kidney development from that of other mesenchymal cells of the renal system.

Authors

Rannar Airik, Markus Bussen, Manvendra K. Singh, Marianne Petry, Andreas Kispert

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Figure 4

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Mislocalization of Tbx18:LacZ expression in Tbx18–/– urogenital systems....
Mislocalization of Tbx18:LacZ expression in Tbx18–/– urogenital systems. (A–E) β-Galactosidase activity staining of a LacZ reporter gene in the Tbx18 locus was analyzed in kidneys at E11.5 (A), in urogenital systems at E12.5 (B) and E14.5 (D), and in transverse sections of E12.5 (C) and E14.5 kidneys (E). P1 and P2 in C indicate sections from the planes shown in B. P1, P2, and P3 in E indicate section planes shown in D. P2high is a higher magnification of P2 in the region of the ureter. Black arrows indicate the ureteric epithelium. (F and G) Hematoxylin and eosin stainings of transverse sections of E14.5 kidneys. Yellow arrows indicate the renal capsule. The boxed regions in F are magnified in G. (H) β-Galactosidase activity staining of 2-day-old cultures of metanephric rudiments that were wild type as well as heterozygous and homozygous for the mutant Tbx18LacZ allele. Slight blue staining of the ureteric epithelium in wild-type mice was due to endogenous β-galactosidase activity. Heterozygotes and homozygotes in A, B, and D were Tbx18LacZ/+ and Tbx18LacZ/Tbx18LacZ, respectively, whereas embryos used for C and E were normalized for the LacZ allele (i.e., Tbx18LacZ/+ and Tbx18/Tbx18LacZ, respectively). cm, condensing (metanephric) mesenchyme. Arrowheads in A and C–H mark localization of Tbx18-positive prospective and definitive ureteral mesenchymal cells in kidneys, urogenital systems, and kidney cultures at the indicated stages. Scale bars: 100 μm (A, C, and E–H), 1,000 μm (B and D).