title: Integrated β-catenin, BMP, PTEN, and Notch signalling patterns the nephron.
abstract: The different segments of the nephron and glomerulus in the kidney balance the processes of water homeostasis, solute recovery, blood filtration, and metabolite excretion. When segment function is disrupted, a range of pathological features are presented. Little is known about nephron patterning during embryogenesis. In this study, we demonstrate that the early nephron is patterned by a gradient in β-catenin activity along the axis of the nephron tubule. By modifying β-catenin activity, we force cells within nephrons to differentiate according to the imposed β-catenin activity level, thereby causing spatial shifts in nephron segments. The β-catenin signalling gradient interacts with the BMP pathway which, through PTEN/PI3K/AKT signalling, antagonises β-catenin activity and promotes segment identities associated with low β-catenin activity. β-catenin activity and PI3K signalling also integrate with Notch signalling to control segmentation: modulating β-catenin activity or PI3K rescues segment identities normally lost by inhibition of Notch. Our data therefore identifies a molecular network for nephron patterning.
authors: Division of Developmental Biology, The Roslin Institute, University of Edinburgh, Easter Bush, United Kingdom.
authors: Nils O
authors: NO
authors: Lindström
authors: Centre for Integrated Physiology, University of Edinburgh, Edinburgh, United Kingdom.
authors: Melanie L
authors: ML
authors: Lawrence
authors: Department of Genetics and Development, Columbia University, New York, United States.
authors: Sally F
authors: SF
authors: Burn
authors: Division of Developmental Biology, The Roslin Institute, University of Edinburgh, Easter Bush, United Kingdom.
authors: Jeanette A
authors: JA
authors: Johansson
authors: Laboratory of Gastroenterology and Hepatology, Erasmus MC, University Medical Centre, Rotterdam, Netherlands.
authors: Elvira R M
authors: ER
authors: Bakker
authors: Department of Invasion and Metastasis, Cancer Research UK Beatson Institute, Glasgow, United Kingdom.
authors: Rachel A
authors: RA
authors: Ridgway
authors: Centre for Integrated Physiology, University of Edinburgh, Edinburgh, United Kingdom.
authors: C-Hong
authors: CH
authors: Chang
authors: Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, United States.
authors: Michele J
authors: MJ
authors: Karolak
authors: Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, United States.
authors: Leif
authors: L
authors: Oxburgh
authors: Division of Developmental Biology, The Roslin Institute, University of Edinburgh, Easter Bush, United Kingdom.
authors: Denis J
authors: DJ
authors: Headon
authors: Beatston Institute for Cancer Research, Glasgow, United Kingdom.
authors: Owen J
authors: OJ
authors: Sansom
authors: Laboratory of Gastroenterology and Hepatology, Erasmus MC, University Medical Centre, Rotterdam, Netherlands.
authors: Ron
authors: R
authors: Smits
authors: Centre for Integrated Physiology, University of Edinburgh, Edinburgh, United Kingdom.
authors: Jamie A
authors: JA
authors: Davies
authors: Division of Developmental Biology, The Roslin Institute, University of Edinburgh, Easter Bush, United Kingdom.
authors: Peter
authors: P
authors: Hohenstein
mesh_terms: D000818:Animals; D019521:Body Patterning / Q000235:genetics*; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D015194:Diffusion Chambers, Culture; D004622:Embryo, Mammalian; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D051379:Mice; D008822:Mice, Transgenic; D009399:Nephrons / Q000166:cytology / Q000254:growth & development / Q000378:metabolism*; D009924:Organ Culture Techniques; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051880:Receptors, Notch / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: D019485:Bone Morphogenetic Proteins; C495267:CTNNB1 protein, mouse; D034741:RNA, Small Interfering; D051880:Receptors, Notch; D051176:beta Catenin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse
keywords: BMP; Notch; PI3K; beta-catenin; developmental biology; kidney development; mouse; patterning; stem cells
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