Johansson, J. et al. (2019) RAL GTPases drive intestinal stem cell function and regeneration through internalization of WNT signalosomes. Cell Stem Cell, 24(4), 592-607.E7. (doi: 10.1016/j.stem.2019.02.002) (PMID:30853556) (PMCID:PMC6459002)
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Abstract
Ral GTPases are RAS effector molecules and by implication a potential therapeutic target for RAS mutant cancer. However, very little is known about their roles in stem cells and tissue homeostasis. Using Drosophila, we identified expression of RalA in intestinal stem cells (ISCs) and progenitor cells of the fly midgut. RalA was required within ISCs for efficient regeneration downstream of Wnt signaling. Within the murine intestine, genetic deletion of either mammalian ortholog, Rala or Ralb, reduced ISC function and Lgr5 positivity, drove hypersensitivity to Wnt inhibition, and impaired tissue regeneration following damage. Ablation of both genes resulted in rapid crypt death. Mechanistically, RALA and RALB were required for efficient internalization of the Wnt receptor Frizzled-7. Together, we identify a conserved role for RAL GTPases in the promotion of optimal Wnt signaling, which defines ISC number and regenerative potential.
Item Type: | Articles |
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Status: | Published |
Refereed: | Yes |
Glasgow Author(s) Enlighten ID: | Cordero, Professor Julia and Yu, Dr Yachuan and Hodder, Michael and Ridgway, Dr Rachel and Naszai, Mr Mate and Sansom, Professor Owen and Campbell, Dr Andrew |
Authors: | Johansson, J., Naszai, M., Hodder, M. C., Pickering, K. A., Miller, B. W., Ridgway, R. A., Yu, Y., Peschard, P., Brachmann, S., Campbell, A. D., Cordero, J. B., and Sansom, O. J. |
College/School: | College of Medical Veterinary and Life Sciences > School of Cancer Sciences |
Journal Name: | Cell Stem Cell |
Publisher: | Elsevier |
ISSN: | 1934-5909 |
ISSN (Online): | 1875-9777 |
Published Online: | 07 March 2019 |
Copyright Holders: | Copyright © 2019 The Authors |
First Published: | First published in Cell Stem Cell 24(4):592-607.E7 |
Publisher Policy: | Reproduced under a Creative Commons License |
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