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There exists, however, little information on whether altered TGF\u03b2 levels actually perturb ureter development. We therefore hypothesised that TGF\u03b2 has functional effects on ureter morphogenesis.\n                    <jats:italic>Tgfb1<\/jats:italic>\n                    ,\n                    <jats:italic>Tgfb2<\/jats:italic>\n                    and\n                    <jats:italic>Tgfb3<\/jats:italic>\n                    transcripts coding for TGF\u03b2 ligands, as well as\n                    <jats:italic>Tgfbr1<\/jats:italic>\n                    and\n                    <jats:italic>Tgfbr2<\/jats:italic>\n                    coding for TGF\u03b2 receptors, were detected by quantitative polymerase chain reaction in embryonic mouse ureters collected over a wide range of stages. As assessed by\n                    <jats:italic>in situ<\/jats:italic>\n                    hybridisation and immunohistochemistry, the two receptors were detected in embryonic urothelia. Next, TGF\u03b21 was added to serum\u2010free cultures of embryonic day 15 mouse ureters. These organs contain immature smooth muscle and urothelial layers and their\n                    <jats:italic>in vivo<\/jats:italic>\n                    potential to grow and acquire peristaltic function can be replicated in serum\u2010free organ culture. Such organs therefore constitute a suitable developmental stage with which to define roles of factors that affect ureter growth and functional differentiation. Exogenous TGF\u03b21 inhibited growth of the ureter tube and generated cocoon\u2010like dysmorphogenesis. RNA sequencing suggested that altered levels of transcripts encoding certain fibroblast growth factors (FGFs) followed exposure to TGF\u03b2. In serum\u2010free organ culture exogenous FGF10 but not FGF18 abrogated certain dysmorphic effects mediated by exogenous TGF\u03b21. To assess whether an endogenous TGF\u03b2 axis functions in developing ureters, embryonic day 15 explants were exposed to TGF\u03b2 receptor chemical blockade; growth of the ureter was enhanced, and aberrant bud\u2010like structures arose from the urothelial tube. The muscle layer was attenuated around these buds, and peristalsis was compromised. To determine whether TGF\u03b2 effects were limited to one stage, explants of mouse embryonic day 13 ureters, more primitive organs, were exposed to exogenous TGF\u03b21, again generating cocoon\u2010like structures, and to TGF\u03b2 receptor blockade, again generating ectopic buds. As for the mouse studies, immunostaining of normal embryonic human ureters detected TGF\u03b2RI and TGF\u03b2RII in urothelia. Collectively, these observations reveal unsuspected regulatory roles for endogenous TGF\u03b2 in embryonic ureters, fine\u2010tuning morphogenesis and functional differentiation. Our results also support the hypothesis that the TGF\u03b2 up\u2010regulation reported in ureter malformations impacts on pathobiology. Further experiments are needed to unravel the intracellular signalling mechanisms involved in these dysmorphic responses. \u00a9 2019 The Authors.\n                    <jats:italic>The Journal of Pathology<\/jats:italic>\n                    published by John Wiley &amp; Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.\n                  <\/jats:p>","DOI":"10.1002\/path.5335","type":"journal-article","created":{"date-parts":[[2019,8,10]],"date-time":"2019-08-10T11:59:21Z","timestamp":1565438361000},"page":"472-484","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Overactivity or blockade of transforming growth factor\u2010\u03b2 each generate a specific ureter malformation"],"prefix":"10.1002","volume":"249","author":[{"given":"Filipa M","family":"Lopes","sequence":"first","affiliation":[{"name":"Division of Cell Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology Medicine and Health University of Manchester  Manchester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neil A","family":"Roberts","sequence":"additional","affiliation":[{"name":"Division of Cell Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology Medicine and Health University of Manchester  Manchester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leo AH","family":"Zeef","sequence":"additional","affiliation":[{"name":"The Bioinformatics Core Facility University of Manchester  Manchester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalie J","family":"Gardiner","sequence":"additional","affiliation":[{"name":"Division of Diabetes, Endocrinology and Gastroenterology, School of Medical Sciences, Faculty of Biology, Medicine and Health University of Manchester  Manchester 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