Teashirt 3 is necessary for ureteral smooth muscle differentiation downstream of SHH and BMP4.
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.
Caubit
Xavier
X
Institut de Biologie du Développement de Marseille-Luminy (IBDML), UMR6216, CNRS, Université de la Méditerranée, Marseille, France.
Lye
Claire M
CM
Martin
Elise
E
Coré
Nathalie
N
Long
David A
DA
Vola
Christine
C
Jenkins
Dagan
D
Garratt
Alistair N
AN
Skaer
Helen
H
Woolf
Adrian S
AS
Fasano
Laurent
L
D000818:Animals; D001483:Base Sequence; D019521:Body Patterning; D055415:Bone Morphogenetic Protein 4 / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D017931:DNA Primers / Q000235:genetics; D004195:Disease Models, Animal; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006869:Hydronephrosis / Q000151:congenital / Q000196:embryology / Q000235:genetics; D008648:Mesoderm / Q000196:embryology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000378:metabolism; D010641:Phenotype; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014513:Ureter / Q000166:cytology / Q000196:embryology* / Q000378:metabolism*
C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; D017931:DNA Primers; D053823:Hedgehog Proteins; C465570:Shh protein, mouse; C534111:Teashirt 3 protein, mouse; D014157:Transcription Factors