JANUS KINASE 3 REGULATES COLONIC DIFFERENTIATION

Abstract

Jak3 is a non‐receptor tyrosine kinase expressed in both hematopoietic and non‐hematopoietic cells. Previously we demonstrated the molecular mechanisms of Jak3 in mucosal wound repair and homeostasis. However the role of Jak3 in intestinal differentiation is not known. In this study, we investigated the in‐vivo significance of Jak3 in intestinal differentiation. We examined the colonic morphology and the expression of different differentiation markers in the intestine. Our results showed that colonic length and colon to body‐weight ratio were significantly reduced in Jak3 KO mice compared to their wild‐type littermates that resulted in increased severity of DSS‐induced colitis. The Enterocytic differentiation marker like villin, carbonic anhydrase, chromagranin, and isoforms of mucin were also analyzed. Expression of villin, chromagranin, and carbonic anhydrase were reduced in Jak3 KO mice. Morphological analysis showed that the number of goblet cells in the crypts of large intestine and crypt lengths from the base of muscularis was reduced in Jak3 KO mice. To determine the molecular mechanism of this impairment, Jak3 interactions with barrier function protein β‐catenin were examined using in vitro model of intestinal epithelial cells. In these cells Jak3 was activated in response to IL‐2 that induced differentiation of goblet cell‐like morphology. IL‐2 also facilitated the interactions of Jak3 with β‐catenin. Knockdown of the Jak3 reduced the tight‐junction localization of β‐catenin with reduced the goblet cell characteristics. Taken together, these data indicate that Jak3 played a crucial role in colonic differentiation through its interactions with β‐catenin.