title: TCF-1-mediated Wnt signaling regulates Paneth cell innate immune defense effectors HD-5 and -6: implications for Crohn's disease.
abstract: 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.
authors.affiliation: Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany;
authors.forename: Julia
authors.initials: J
authors.lastname: Beisner
authors.affiliation: Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany;
authors.forename: Zora
authors.initials: Z
authors.lastname: Teltschik
authors.affiliation: Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany;
authors.forename: Maureen J
authors.initials: MJ
authors.lastname: Ostaff
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, Netherlands;
authors.forename: Machteld M
authors.initials: MM
authors.lastname: Tiemessen
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, Netherlands;
authors.forename: Frank J T
authors.initials: FJ
authors.lastname: Staal
authors.affiliation: Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany;
authors.forename: Guoxing
authors.initials: G
authors.lastname: Wang
authors.affiliation: Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany; Department of Pediatrics, Akershus University Hospital, Oslo University Hospital, Ullevål, Oslo, Norway;
authors.forename: Michael
authors.initials: M
authors.lastname: Gersemann
authors.affiliation: Department of Pediatrics, Akershus University Hospital, Oslo University Hospital, Ullevål, Oslo, Norway;
authors.forename: Gori
authors.initials: G
authors.lastname: Perminow
authors.affiliation: University of Oslo, Epigen, Faculty Division Akershus University Hospital and Medical Clinic, Gastroenterology, Oslo University Hospital, Rikshospitalet, Oslo, Norway; and.
authors.forename: Morten H
authors.initials: MH
authors.lastname: Vatn
authors.affiliation: Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany; University of Tuebingen, Tuebingen, Germany; Department of Clinical Pharmacology, Institute of Experimental and Clinical Pharmacology and Toxicology, University Hospital, Tuebingen, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Schwab
authors.affiliation: Department of Gastroenterology, Robert Bosch Hospital, Stuttgart, Germany;
authors.forename: Eduard F
authors.initials: EF
authors.lastname: Stange
authors.affiliation: Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany; University of Tuebingen, Tuebingen, Germany; Department of Gastroenterology, Robert Bosch Hospital, Stuttgart, Germany; jan.wehkamp@med.uni-tuebingen.de.
authors.forename: Jan
authors.initials: J
authors.lastname: Wehkamp
mesh_terms: D000293:Adolescent; D000818:Animals; D001665:Binding Sites; D018938:Caco-2 Cells; D003424:Crohn Disease / Q000378:metabolism*; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D007082:Ileum / Q000378:metabolism / Q000473:pathology; D007583:Jejunum / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009928:Organ Specificity; D019879:Paneth Cells / Q000378:metabolism*; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051822:T Cell Transcription Factor 1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D060449:Wnt Signaling Pathway; D023084:alpha-Defensins / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D011498:Protein Precursors; D012333:RNA, Messenger; D051822:T Cell Transcription Factor 1; D023084:alpha-Defensins; D051176:beta Catenin; C059569:cryptdin
keywords: Crohn's disease; Paneth cells; TCF-1; Wnt signaling; defensins