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

Cell Death Differ. 2011 Dec;18(12):1934-43. doi: 10.1038/cdd.2011.77. Epub 2011 Jun 3.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Caspase 3 / metabolism
  • Cell Movement
  • Cell Proliferation
  • Cell Survival*
  • Enzyme Activation
  • Gene Expression
  • Intestinal Mucosa / cytology*
  • Intestinal Mucosa / metabolism
  • Intestine, Small / cytology*
  • Intestine, Small / metabolism
  • Male
  • Mice
  • Mice, 129 Strain
  • Mice, Inbred C3H
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nuclear Proteins / metabolism
  • Polycomb Repressive Complex 1
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism
  • Repressor Proteins / metabolism
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism
  • STAT3 Transcription Factor / physiology*
  • Stem Cells / metabolism
  • Stem Cells / physiology*
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism
  • Up-Regulation


  • Bmi1 protein, mouse
  • Myc protein, mouse
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-myc
  • Repressor Proteins
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • Tumor Suppressor Protein p53
  • Polycomb Repressive Complex 1
  • Casp3 protein, mouse
  • Caspase 3