Off-target activity of the 8kb Dmp1-Cre results in the deletion ofTsc1gene in mouse intestinal mesenchyme.

Abstract

The Dmp1-Cre mouse, expressing Cre from an 8-kb DNA fragment of the mouse Dmp1 gene, is a common tool to study gene functions in osteocytes. Here we report that the deletion of Tsc1 (TSC complex subunit 1) by 8kb Dmp1-Cre causes rectal prolapse in mice. Histological examination shows the presence of colon polyps in Tsc1-deficient mice in association with significantly larger colon and narrower lumen, which recapitulates the common polyps pathology in Tuberous Sclerosis, an autosomal dominant disorder caused by mutations in either TSC1 or TSC2. The intestine in Tsc1-deficient mice is also enlarged with the presence of taller villi. Using the Ai14 reporter mice that express a red fluorescence protein upon Cre recombination, we show that 8kb Dmp1-Cre activity is evident in portion of the mesenchyme of the colon and small intestine. Lastly, our data show that Tsc1 deletion by Dmp1-Cre leads to an increased proliferation in the mesenchyme of colon, which at least partly contributes to the polyps pathology seen in this mouse model and is likely a contributing factor of the polyps in Tuberous Sclerosis.