Integrated β-catenin, BMP, PTEN, and Notch signalling patterns the nephron
Nils O Lindström,
Melanie L Lawrence,
Sally F Burn,
Jeanette A Johansson,
Elvira RM Bakker,
Rachel A Ridgway,
C-Hong Chang,
Michele J Karolak,
Leif Oxburgh,
Denis J Headon,
Owen J Sansom,
Ron Smits,
Jamie A Davies,
Peter Hohenstein
Affiliations
Nils O Lindström
Division of Developmental Biology, The Roslin Institute, University of Edinburgh, Easter Bush, United Kingdom; MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, Edinburgh, United Kingdom
Melanie L Lawrence
Centre for Integrated Physiology, University of Edinburgh, Edinburgh, United Kingdom
Sally F Burn
Department of Genetics and Development, Columbia University, New York, United States
Jeanette A Johansson
Division of Developmental Biology, The Roslin Institute, University of Edinburgh, Easter Bush, United Kingdom
Elvira RM Bakker
Laboratory of Gastroenterology and Hepatology, Erasmus MC, University Medical Centre, Rotterdam, Netherlands
Rachel A Ridgway
Department of Invasion and Metastasis, Cancer Research UK Beatson Institute, Glasgow, United Kingdom
C-Hong Chang
Centre for Integrated Physiology, University of Edinburgh, Edinburgh, United Kingdom
Michele J Karolak
Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, United States
Leif Oxburgh
Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, United States
Denis J Headon
Division of Developmental Biology, The Roslin Institute, University of Edinburgh, Easter Bush, United Kingdom
Owen J Sansom
Beatston Institute for Cancer Research, Glasgow, United Kingdom
Ron Smits
Laboratory of Gastroenterology and Hepatology, Erasmus MC, University Medical Centre, Rotterdam, Netherlands
Jamie A Davies
Centre for Integrated Physiology, University of Edinburgh, Edinburgh, United Kingdom
Division of Developmental Biology, The Roslin Institute, University of Edinburgh, Easter Bush, United Kingdom; MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, Edinburgh, United Kingdom
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.
