Overactivity or blockade of transforming growth factor-? each generate a specific ureter malformation.

ABSTRACT: Transforming growth factor-? (TGF?) has been reported to be dysregulated in malformed ureters. There exists, however, little information on whether altered TGF? levels actually perturb ureter development. We therefore hypothesised that TGF? has functional effects on ureter morphogenesis. Tgfb1, Tgfb2 and Tgfb3 transcripts coding for TGF? ligands, as well as Tgfbr1 and Tgfbr2 coding for TGF? receptors, were detected by quantitative polymerase chain reaction in embryonic mouse ureters collected over a wide range of stages. As assessed by in situ hybridisation and immunohistochemistry, the two receptors were detected in embryonic urothelia. Next, TGF?1 was added to serum-free cultures of embryonic day 15 mouse ureters. These organs contain immature smooth muscle and urothelial layers and their in vivo potential to grow and acquire peristaltic function can be replicated in serum-free 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?1 inhibited growth of the ureter tube and generated cocoon-like dysmorphogenesis. RNA sequencing suggested that altered levels of transcripts encoding certain fibroblast growth factors (FGFs) followed exposure to TGF?. In serum-free organ culture exogenous FGF10 but not FGF18 abrogated certain dysmorphic effects mediated by exogenous TGF?1. To assess whether an endogenous TGF? axis functions in developing ureters, embryonic day 15 explants were exposed to TGF? receptor chemical blockade; growth of the ureter was enhanced, and aberrant bud-like structures arose from the urothelial tube. The muscle layer was attenuated around these buds, and peristalsis was compromised. To determine whether TGF? effects were limited to one stage, explants of mouse embryonic day 13 ureters, more primitive organs, were exposed to exogenous TGF?1, again generating cocoon-like structures, and to TGF? receptor blockade, again generating ectopic buds. As for the mouse studies, immunostaining of normal embryonic human ureters detected TGF?RI and TGF?RII in urothelia. Collectively, these observations reveal unsuspected regulatory roles for endogenous TGF? in embryonic ureters, fine-tuning morphogenesis and functional differentiation. Our results also support the hypothesis that the TGF? up-regulation reported in ureter malformations impacts on pathobiology. Further experiments are needed to unravel the intracellular signalling mechanisms involved in these dysmorphic responses. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

SUBMITTER: Lopes FM 

PROVIDER: S-EPMC6900140 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature