Absolute requirement for STAT3 function in small-intestine crypt stem cell survival

Matthews, J.R., Sansom, O.J. and Clarke, A.R. (2011) Absolute requirement for STAT3 function in small-intestine crypt stem cell survival. Cell Death and Differentiation, 18(12), pp. 1934-1943. (doi:10.1038/cdd.2011.77)

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Publisher's URL: http://dx.doi.org/10.1038/cdd.2011.77

Abstract

The transcription factor signal transducer and activator of transcription 3 (STAT3) is frequently activated in human cancers. Interestingly, STAT3 also maintains the pluripotency and self-renewal of murine embryonic stem cells, and several tissue stem cell types. To investigate whether STAT3 also maintains the small-intestine crypt stem cell, we conditionally inactivated a Floxed Stat3 allele (Stat3(fl)) in murine small-intestine crypt stem cells. Following Cre recombinase expression, apoptosis increased in Stat3(fl/-) experimental crypts relative to Stat3(wt/-) controls before declining. Control Stat3(wt/-) mice carrying a Flox-STOP LacZ reporter transgene stably expressed LacZ after Cre induction. In contrast, Stat3(fl/-) intestine LacZ expression initially increased modestly, before declining to background levels. Quantitative PCRs revealed a similar transient in recombined Stat3(fl) allele levels. Long-term bromodeoxyuridine labelling directly demonstrated that functional STAT3 is required for +4 to +6 region label-retaining small-intestine stem cell survival. Rapid clearance of recombined Stat3(fl/-) cells involves apoptosis potentially induced by elevated c-Myc in non-recombined cells and involves elevated p53 expression and caspase 3 activation. Intriguingly, Stat3(fl/-) intestine recombination triggered dramatically upregulated polycomb transcriptional repressor Bmi1 - potentially accelerating recombined crypt repopulation. In summary, STAT3 activity is absolutely required for small-intestine crypt stem cell survival at both the +4 to +6 label-retaining and crypt base columnar cell locations.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Sansom, Professor Owen
Authors: Matthews, J.R., Sansom, O.J., and Clarke, A.R.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Cell Death and Differentiation
ISSN:1350-9047
ISSN (Online):1476-5403
Published Online:03 June 2011

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