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Vol. 20, Issue 21, 4489-4499, November 1, 2009

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CASK Deletion in Intestinal Epithelia Causes Mislocalization of LIN7C and the DLG1/Scrib Polarity Complex without Affecting Cell Polarity

Department of Pathology, Yale University School of Medicine, New Haven, CT 06520

Submitted April 8, 2009; Revised August 3, 2009; Accepted August 25, 2009
Monitoring Editor: Asma Nusrat

CASK is the mammalian ortholog of LIN2, a component of the LIN2/7/10 protein complex that targets epidermal growth factor receptor (EGFR) to basolateral membranes in Caenorhabditis elegans. A member of the MAGUK family of scaffolding proteins, CASK resides at basolateral membranes in polarized epithelia. Its interaction with LIN7 is evolutionarily conserved. In addition, CASK forms a complex with another MAGUK, the DLG1 tumor suppressor. Although complete knockout of CASK is lethal, the gene is X-linked, enabling us to generate heterozygous female adults that are mosaic for its expression. We also generated intestine-specific CASK knockout mice. Immunofluorescence analysis revealed that in intestine, CASK is not required for epithelial polarity or differentiation but is necessary for the basolateral localization of DLG1 and LIN7C. However, the subcellular distributions of DLG1 and LIN7C are independent of CASK in the stomach. Moreover, CASK and LIN7C show normal localization in dlg1^–/– intestine. Despite the disappearance of basolateral LIN7C in CASK-deficient intestinal crypts, this epithelium retains normal localization of LIN7A/B, EGFR and ErbB-2. Finally, crypt-to-villus migration rates are unchanged in CASK-deficient intestinal epithelium. Thus, CASK expression and the appropriate localization of DLG1 are not essential for either epithelial polarity or intestinal homeostasis in vivo.

* Present address: Brigham and Women's Hospital, Division of Hematology, 75 Francis Street, Boston, MA 02115.

Address correspondence to: Zenta Walther (zenta.walther{at}yale.edu).

Abbreviations used: APC, adenomatous polyposis coli; EGFR, epidermal growth factor receptor; KID, kinase interaction domain; MAGUK, membrane-associated guanylate kinase.