title: Krüppel-like factor 5 is important for maintenance of crypt architecture and barrier function in mouse intestine.
abstract: OBJECTIVE
  Krüppel-like factor 5 (KLF5) is transcription factor that is expressed by dividing epithelial cells of the intestinal epithelium. KLF5 promotes proliferation in vitro and in vivo and is induced by mitogens and various stress stimuli. To study the role of KLF5 in intestinal epithelial homeostasis, we examined the phenotype of mice with conditional deletion of Klf5 in the gut.
  
  
  METHODS
  Mice were generated with intestinal-specific deletion of Klf5 (Vil-Cre;Klf5fl/fl). Morphologic changes in the small intestine and colon were examined by immunohistochemistry, immunoblotting, and real-time polymerase chain reaction.
  
  
  RESULTS
  Klf5 mutant mice were born at a normal Mendelian ratio but had high mortality compared with controls. Complete deletion of Klf5 from the intestinal mucosa resulted in neonatal lethality that corresponded with an absence of epithelial proliferation. Variegated intestinal-specific deletion of Klf5 in adult mice resulted in morphologic changes that included a regenerative phenotype, impaired barrier function, and inflammation. Adult mutant mice exhibited defects in epithelial differentiation and migration. These changes were associated with reduced expression of Caudal type homeobox (Cdx) 1, Cdx2, and Eph and ephrin signaling proteins. Concomitantly, Wnt signaling to β-catenin was reduced. Proliferation in regenerative crypts was associated with increased expression of the progenitor cell marker Sox9.
  
  
  CONCLUSIONS
  Deletion of Klf5 in the gut epithelium of mice demonstrated that KLF5 maintains epithelial proliferation, differentiation, and cell positioning along the crypt radial axis. Morphologic changes that occur with deletion of Klf5 are associated with disruption of canonical Wnt signaling and increased expression of Sox9.
authors.affiliation: Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Beth B
authors.initials: BB
authors.lastname: McConnell
authors.forename: Samuel S
authors.initials: SS
authors.lastname: Kim
authors.forename: Ke
authors.initials: K
authors.lastname: Yu
authors.forename: Amr M
authors.initials: AM
authors.lastname: Ghaleb
authors.forename: Norifumi
authors.initials: N
authors.lastname: Takeda
authors.forename: Ichiro
authors.initials: I
authors.lastname: Manabe
authors.forename: Asma
authors.initials: A
authors.lastname: Nusrat
authors.forename: Ryozo
authors.initials: R
authors.lastname: Nagai
authors.forename: Vincent W
authors.initials: VW
authors.lastname: Yang
mesh_terms: D000818:Animals; D015153:Blotting, Western; D000071616:CDX2 Transcription Factor; D002454:Cell Differentiation; D002465:Cell Movement; D049109:Cell Proliferation; D003106:Colon / Q000378:metabolism* / Q000473:pathology; D036342:Ephrins / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D005838:Genotype; D018398:Homeodomain Proteins / Q000378:metabolism; D007082:Ileum / Q000378:metabolism* / Q000473:pathology; D007150:Immunohistochemistry; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000473:pathology; D051741:Kruppel-Like Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010539:Permeability; D010641:Phenotype; D016133:Polymerase Chain Reaction; D036081:Receptors, Eph Family / Q000378:metabolism; D012038:Regeneration; D055758:SOX9 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
chemical_list: D000071616:CDX2 Transcription Factor; C495267:CTNNB1 protein, mouse; C491272:Cdx1 protein, mouse; C487514:Cdx2 protein, mouse; D036342:Ephrins; D018398:Homeodomain Proteins; C118391:Klf5 protein, mouse; D051741:Kruppel-Like Transcription Factors; D055758:SOX9 Transcription Factor; C527933:Sox9 protein, mouse; D014157:Transcription Factors; D051153:Wnt Proteins; D051176:beta Catenin; D036081:Receptors, Eph Family