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Colitis, hypothyroidism, and immunological alterations in mice deficient in glycan branching enzymes


A majority of my dissertation research has focused on investigating why multiple glycosyltransferases with the ability to produce Core 2 O-glycans, the Core 2 beta-1,6-N -acetylglucosaminyltransferases (C2GnTs), have been conserved. For these studies I have utilized mice singly and multiply deficient in C2GnTs. Our results begin to explain why these three separate glycosyltransferases have been conserved, as each singly deficient strain exhibits distinct phenotypes. C2GnT1 has previously been shown to be required for normal selectin ligand formation. We found that absence of C2GnT2 results in reduced mucosal barrier function and increased disease pathogenesis following treatment with dextran sodium sulfate to induce colitis. C2GnT2-deficient mice also have reduced circulating and mucosal immunoglobulins, likely resulting from decreased antigen-specific humoral responses to mucosal but not parenteral antigens. In contrast, mice deficient for C2GnT3 exhibited increased dominance in the tube test for social dominance linked to reduced Thyroxine abundance in circulation. Remarkably, we found that mice deficient for all three C2GnTs were viable and lacked all Core 2 O- glycan structures. Analysis of O-glycan structures present in the various singly deficient models revealed that all 3 C2GnTs contribute to Core 2 O-glycan biosynthesis in vivo, albeit to differing degrees. We further found that loss of C2GnTs resulted in unexpected alterations in O- glycosylation, including increased abundance of elongated Core 1 O-glycans. Furthermore, elongated O-mannose structures were unexpectedly present in stomach tissue from C2GnT2-deficient mice or mice lacking all three C2GnTs

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