TCF-1-mediated Wnt signaling regulates Paneth cell innate immune defense effectors HD-5 and -6: implications for Crohn's disease

Am J Physiol Gastrointest Liver Physiol. 2014 Sep 1;307(5):G487-98. doi: 10.1152/ajpgi.00347.2013. Epub 2014 Jul 3.


Wnt signaling regulates small intestinal stem cell maintenance and Paneth cell differentiation. In patients with ileal Crohn's disease (CD), a decrease of Paneth cell α-defensins has been observed that is partially caused by impaired TCF-4 and LRP6 function. Here we show reduced expression of the Wnt signaling effector TCF-1 (also known as TCF-7) in patients with ileal CD. Reporter gene assays and in vitro promoter binding analysis revealed that TCF-1 activates α-defensin HD-5 and HD-6 transcription in cooperation with β-catenin and that activation is mediated by three distinct TCF binding sites. EMSA analysis showed binding of TCF-1 to the respective motifs. In ileal CD patients, TCF-1 mRNA expression levels were significantly reduced. Moreover, we found specifically reduced expression of active TCF-1 mRNA isoforms. Tcf-1 knockout mice exhibited reduced cryptdin expression in the jejunum, which was not consistently seen at other small intestinal locations. Our data provide evidence that TCF-1-mediated Wnt signaling is disturbed in small intestinal CD, which might contribute to the observed barrier dysfunction in the disease.

Keywords: Crohn's disease; Paneth cells; TCF-1; Wnt signaling; defensins.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Animals
  • Binding Sites
  • Caco-2 Cells
  • Crohn Disease / metabolism*
  • Female
  • HEK293 Cells
  • Humans
  • Ileum / metabolism
  • Ileum / pathology
  • Jejunum / metabolism
  • Jejunum / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Organ Specificity
  • Paneth Cells / metabolism*
  • Protein Precursors / genetics
  • Protein Precursors / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • T Cell Transcription Factor 1 / chemistry
  • T Cell Transcription Factor 1 / genetics
  • T Cell Transcription Factor 1 / metabolism*
  • Wnt Signaling Pathway*
  • alpha-Defensins / genetics
  • alpha-Defensins / metabolism*
  • beta Catenin / genetics
  • beta Catenin / metabolism


  • Protein Precursors
  • RNA, Messenger
  • T Cell Transcription Factor 1
  • alpha-Defensins
  • beta Catenin
  • cryptdin