Overactivity or blockade of transforming growth factor-β each generate a specific ureter malformationCitation formats

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Overactivity or blockade of transforming growth factor-β each generate a specific ureter malformation. / Lopes, Filipa; Roberts, Neil; Zeef, Leo; Gardiner, Natalie; Woolf, Adrian S.

In: Journal of Pathology, 2019.

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@article{026b5b803d2a43c4b0160751abb9aa96,
title = "Overactivity or blockade of transforming growth factor-β each generate a specific ureter malformation",
abstract = "Transforming growth factor-β (TGFβ) has been reported to be dysregulated in malformed ureters. There exists, however, little information on whether altered TGFβ levels actually perturb ureter development. We therefore hypothesised that TGFβ has functional effects on ureter morphogenesis. Tgfb1, Tgfb2, and Tgfb3 transcripts coding for TGFβ 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, TGFβ1 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 TGFβ1 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 TGFβ. In serum-free organ culture exogenous FGF10 but not FGF18 abrogated certain dysmorphic effects mediated by exogenous TGFβ1. To assess whether an endogenous TGFβ axis functions in developing ureters, embryonic day 15 explants were exposed to TGFβ 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 TGFβ effects were limited to one stage, explants of mouse embryonic day 13 ureters, more primitive organs, were exposed to exogenous TGFβ1, again generating cocoon-like structures, and to TGFβ receptor blockade, again generating ectopic buds. As for the mouse studies, immunostaining of normal embryonic human ureters detected TGFβRI and TGFβRII in urothelia. Collectively, these observations reveal unsuspected regulatory roles for endogenous TGFβ in embryonic ureters, fine-tuning morphogenesis and functional differentiation. Our results also support the hypothesis that the TGFβ upregulation reported in ureter malformations impacts on pathobiology. Further experiments are needed to unravel the intracellular signalling mechanisms involved in these dysmorphic responses.",
keywords = "embryo, growth factor, human, malformation, mouse, urothelium",
author = "Filipa Lopes and Neil Roberts and Leo Zeef and Natalie Gardiner and Woolf, {Adrian S.}",
year = "2019",
doi = "10.1002/path.5335",
language = "English",
journal = "Journal of Pathology",
issn = "0022-3417",
publisher = "John Wiley & Sons Ltd",

}

RIS

TY - JOUR

T1 - Overactivity or blockade of transforming growth factor-β each generate a specific ureter malformation

AU - Lopes, Filipa

AU - Roberts, Neil

AU - Zeef, Leo

AU - Gardiner, Natalie

AU - Woolf, Adrian S.

PY - 2019

Y1 - 2019

N2 - Transforming growth factor-β (TGFβ) has been reported to be dysregulated in malformed ureters. There exists, however, little information on whether altered TGFβ levels actually perturb ureter development. We therefore hypothesised that TGFβ has functional effects on ureter morphogenesis. Tgfb1, Tgfb2, and Tgfb3 transcripts coding for TGFβ 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, TGFβ1 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 TGFβ1 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 TGFβ. In serum-free organ culture exogenous FGF10 but not FGF18 abrogated certain dysmorphic effects mediated by exogenous TGFβ1. To assess whether an endogenous TGFβ axis functions in developing ureters, embryonic day 15 explants were exposed to TGFβ 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 TGFβ effects were limited to one stage, explants of mouse embryonic day 13 ureters, more primitive organs, were exposed to exogenous TGFβ1, again generating cocoon-like structures, and to TGFβ receptor blockade, again generating ectopic buds. As for the mouse studies, immunostaining of normal embryonic human ureters detected TGFβRI and TGFβRII in urothelia. Collectively, these observations reveal unsuspected regulatory roles for endogenous TGFβ in embryonic ureters, fine-tuning morphogenesis and functional differentiation. Our results also support the hypothesis that the TGFβ upregulation reported in ureter malformations impacts on pathobiology. Further experiments are needed to unravel the intracellular signalling mechanisms involved in these dysmorphic responses.

AB - Transforming growth factor-β (TGFβ) has been reported to be dysregulated in malformed ureters. There exists, however, little information on whether altered TGFβ levels actually perturb ureter development. We therefore hypothesised that TGFβ has functional effects on ureter morphogenesis. Tgfb1, Tgfb2, and Tgfb3 transcripts coding for TGFβ 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, TGFβ1 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 TGFβ1 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 TGFβ. In serum-free organ culture exogenous FGF10 but not FGF18 abrogated certain dysmorphic effects mediated by exogenous TGFβ1. To assess whether an endogenous TGFβ axis functions in developing ureters, embryonic day 15 explants were exposed to TGFβ 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 TGFβ effects were limited to one stage, explants of mouse embryonic day 13 ureters, more primitive organs, were exposed to exogenous TGFβ1, again generating cocoon-like structures, and to TGFβ receptor blockade, again generating ectopic buds. As for the mouse studies, immunostaining of normal embryonic human ureters detected TGFβRI and TGFβRII in urothelia. Collectively, these observations reveal unsuspected regulatory roles for endogenous TGFβ in embryonic ureters, fine-tuning morphogenesis and functional differentiation. Our results also support the hypothesis that the TGFβ upregulation reported in ureter malformations impacts on pathobiology. Further experiments are needed to unravel the intracellular signalling mechanisms involved in these dysmorphic responses.

KW - embryo

KW - growth factor

KW - human

KW - malformation

KW - mouse

KW - urothelium

U2 - 10.1002/path.5335

DO - 10.1002/path.5335

M3 - Article

JO - Journal of Pathology

JF - Journal of Pathology

SN - 0022-3417

ER -