Lgr5+ intestinal stem cells reside in an unlicensed G1 phase

Carroll, Thomas D., Newton, Ian P., Chen, Yu, Blow, John ORCID: https://orcid.org/0000-0002-9524-5849 and Näthke, Inke (2018) Lgr5+ intestinal stem cells reside in an unlicensed G1 phase. Journal of Cell Biology, 217 (5). pp. 1667-1685. ISSN 0021-9525

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Abstract

During late mitosis and the early G1 phase, the origins of replication are licensed by binding to double hexamers of MCM2-7. In this study, we investigated how licensing and proliferative commitment are coupled in the epithelium of the small intestine. We developed a method for identifying cells in intact tissue containing DNA-bound MCM2-7. Interphase cells above the transit-amplifying compartment had no DNA-bound MCM2-7, but still expressed the MCM2-7 protein, suggesting that licensing is inhibited immediately upon differentiation. Strikingly, we found most proliferative Lgr5 + stem cells are in an unlicensed state. This suggests that the elongated cell-cycle of intestinal stem cells is caused by an increased G 1 length, characterized by dormant periods with unlicensed origins. Significantly, the unlicensed state is lost in Apc-mutant epithelium, which lacks a functional restriction point, causing licensing immediately upon G1 entry. We propose that the unlicensed G1 phase of intestinal stem cells creates a temporal window when proliferative fate decisions can be made.

Item Type:	Article
Additional Information:	The imaging facility is funded by the Welcome Trust Technology Platform award (097945/B/11/Z) and Welcome Trust award (101468/Z/13/Z). We thank Dr Rosemary Clarke and the Dundee Flow Cytometry Facility for support with flow cytometry, cell sorting and analysis. We also thank Dr Richard Mort (University of Edinburgh) for Fucci2aR mouse tissue. This work was supported by a programme grant from Cancer Research UK to I.N (C430/A11243) and to J.J.B (C303/A14301), Wellcome Trust grant WT096598MA and an MRC studentship award to T.D.C.
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Depositing User:	LivePure Connector
Date Deposited:	10 Jun 2024 14:30
Last Modified:	22 Jul 2024 12:32
URI:	https://ueaeprints.uea.ac.uk/id/eprint/95458
DOI:	10.1083/jcb.201708023

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