title: Pinin modulates expression of an intestinal homeobox gene, Cdx2, and plays an essential role for small intestinal morphogenesis.
abstract: Pinin (Pnn), a nuclear speckle-associated protein, has been shown to function in maintenance of epithelial integrity through altering expression of several key adhesion molecules. Here we demonstrate that Pnn plays a crucial role in small intestinal development by influencing expression of an intestinal homeobox gene, Cdx2. Conditional inactivation of Pnn within intestinal epithelia resulted in significant downregulation of a caudal type homeobox gene, Cdx2, leading to obvious villus dysmorphogenesis and severely disrupted epithelial differentiation. Additionally, in Pnn-deficient small intestine, we observed upregulated Tcf/Lef reporter activity, as well as misregulated expression/distribution of beta-catenin and Tcf4. Since regulation of Cdx gene expression has been closely linked to Wnt/beta-catenin signaling activity, we explored the possibility of Pnn's interaction with beta-catenin, a major effector of the canonical Wnt signaling pathway. Co-immunoprecipitation assays revealed that Pnn, together with its interaction partner CtBP2, a transcriptional co-repressor, was in a complex with beta-catenin. Moreover, both of these proteins were found to be recruited to the proximal promoter area of Cdx2. Taken together, our results suggest that Pnn is essential for tight regulation of Wnt signaling and Cdx2 expression during small intestinal development.
authors.affiliation: Department of Anatomy and Cell Biology, University of Florida College of Medicine, Gainesville, FL, USA.
authors.forename: Jeong-Hoon
authors.initials: JH
authors.lastname: Joo
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Taxter
authors.forename: Gustavo C
authors.initials: GC
authors.lastname: Munguba
authors.forename: Yong H
authors.initials: YH
authors.lastname: Kim
authors.forename: Kanthi
authors.initials: K
authors.lastname: Dhaduvai
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Dunn
authors.forename: William J
authors.initials: WJ
authors.lastname: Degan
authors.forename: S Paul
authors.initials: SP
authors.lastname: Oh
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Sugrue
mesh_terms: D000818:Animals; D000071616:CDX2 Transcription Factor; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins; D004622:Embryo, Mammalian / Q000378:metabolism; D005801:Genes, Homeobox; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D007421:Intestine, Small / Q000254:growth & development*; D051379:Mice; D009024:Morphogenesis / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D051820:TCF Transcription Factors / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D000071616:CDX2 Transcription Factor; C487514:Cdx2 protein, mouse; D015815:Cell Adhesion Molecules; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D009687:Nuclear Proteins; C491175:Pnn protein, mouse; D051820:TCF Transcription Factors; D014157:Transcription Factors; D051153:Wnt Proteins; D051176:beta Catenin