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ROLE OF PTEN PHOSPHATASE IN INTESTINAL HOMEOSTASIS, EPITHELIAL DIFFERENTIATION AND TUMOUR INITIATION

S Roy, MJ Langlois, C Jones, F Boudreau, BA Auclair, J Carrier, N Rivard, N Perreault
Équipe IRSC sur l’épithélium digestif Département d’Anatomie et de Biologie Cellulaire, FMSS, Université de Sherbrooke

BACKGROUND: PTEN is a tumour suppressor gene located in a chromosomal region frequently altered in human tumours (10q23). PTEN dephosphorylates phosphatidylinositols resulting from phosphatidylinositol 3-kinase activation. Germinal mutations of PTEN have been identified in Cowden Disease, characterized by the development of hamartomatous polyps in the digestive tract.
AIM: To investigate the role of Pten in the regulation of cell function and maintenance of the intestinal epithelium.
METHODS AND RESULTS: With the use of the Cre/loxP system, we have generated a mouse with the Pten gene deleted exclusively in the intestinal epithelium. Macroscopic analysis revealed a dramatic increase in the length of the GI tract while H&E staining showed multiplication and elongation of the crypt compartment as well as an important lengthening of the villi in Pten mutant mice. Alcian Blue staining showed an increase in the number of goblet cells which were found to be consistently larger in the mutant mice. QPCR analysis revealed a significant increase in Klf4 which is known to play a crucial role in goblet cell terminal differentiation. We next performed an immunostaining with an anti-lysozyme antibody which revealed a reduction in Paneth cell secretory granule content in Pten mutant mice. QPCR analysis showed a significant decrease in MMP7, a known factor essential for Paneth cell terminal differentiation. In order to assess the potential role of Pten in intestinal neoplasia, we crossed the Villin-Cre;Pten^loxP/loxP mice with APC^Min mice which were sacrificed at 60-days and assessed for the formation of adenomas. Counts revealed a significant increase (11.6 fold) in the number of intestinal polyps in double mutant mice when compared with control APC^Min mice.
CONCLUSION: Our results strongly suggest an important role for intestinal epithelial Pten signalization in the maintenance of general intestinal architecture, epithelial cytodifferentiation and intestinal tumorigenesis.

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