RAL GTPases drive intestinal stem cell function and regeneration through internalization of WNT signalosomes

Johansson, J. et al. (2019) RAL GTPases drive intestinal stem cell function and regeneration through internalization of WNT signalosomes. Cell Stem Cell, (doi:10.1016/j.stem.2019.02.002) (PMID:30853556) (Early Online Publication)

Johansson, J. et al. (2019) RAL GTPases drive intestinal stem cell function and regeneration through internalization of WNT signalosomes. Cell Stem Cell, (doi:10.1016/j.stem.2019.02.002) (PMID:30853556) (Early Online Publication)

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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
Status:Early Online Publication
Refereed:Yes
Glasgow Author(s) Enlighten ID:Cordero, Dr Julia and Yu, Dr Yachuan and Ridgway, Dr Rachel and Campbell, Mr Andrew and Naszai, Mr Mate and Sansom, Professor Owen and Hodder, Michael
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 > Institute 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 2019
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
633022Regulation of stem cell function during tissue homeostasis and transformationJulia CorderoWellcome Trust (WELLCOTR)104103/Z/14/ZRI CANCER SCIENCES