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First published online September 5, 2008
doi: 10.1242/10.1242/dev.022442

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Teashirt 3 is necessary for ureteral smooth muscle differentiation downstream of SHH and BMP4

Xavier Caubit^1,*, Claire M. Lye^2,*, Elise Martin^1,*, Nathalie Coré¹, David A. Long², Christine Vola¹, Dagan Jenkins³, Alistair N. Garratt⁴, Helen Skaer⁵, Adrian S. Woolf^2, and Laurent Fasano^1,

¹ Institut de Biologie du Développement de Marseille-Luminy (IBDML), UMR6216, CNRS, Université de la Méditerranée, F-13288 Marseille cedex 09, France.
² Nephro-Urology Unit, UCL Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK.
³ Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.
⁴ Max-Delbrueck-Center for Molecular Medicine, Robert-Roessle-Strasse 10, 13125 Berlin, Germany.
⁵ Department of Zoology, University of Cambridge, Downing Street, Cambridge CB2 3EJ, UK.

Authors for correspondence (e-mails: a.woolf{at}ich.ucl.ac.uk; fasano{at}ibdml.univ-mrs.fr)

Accepted 30 July 2008

Ureteric contractions propel foetal urine from the kidney to the urinary bladder. Here, we show that mouse ureteric smooth muscle cell (SMC) precursors express the transcription factor teashirt 3 (TSHZ3), and that Tshz3-null mutant mice have congenital hydronephrosis without anatomical obstruction. Ex vivo, the spontaneous contractions that occurred in proximal segments of wild-type embryonic ureter explants were absent in Tshz3 mutant ureters. In vivo, prior to the onset of hydronephrosis, mutant proximal ureters failed to express contractile SMC markers, whereas these molecules were detected in controls. Mutant embryonic ureters expressed Shh and Bmp4 transcripts as normal, with appropriate expression of Ptch1 and pSMAD1/5/8 in target SM precursors, whereas myocardin, a key regulator for SMC differentiation, was not expressed in Tshz3-null ureters. In wild-type embryonic renal tract explants, exogenous BMP4 upregulated Tshz3 and myocardin expression. More interestingly, in Tshz3 mutant renal tract explants, exogenous BMP4 did not improve the Tshz3 phenotype. Thus, Tshz3 is required for proximal ureteric SMC differentiation downstream of SHH and BMP4. Furthermore, the Tshz3 mutant mouse model of `functional' urinary obstruction resembles congenital pelvi-ureteric junction obstruction, a common human malformation, suggesting that TSHZ, or related, gene variants may contribute to this disorder.

Key words: Gene targeting, Teashirt 3 (Tshz3), UPJO, Ureter, Smooth muscle

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