The Role of Alpha 1,3 Fucosyltransferases in Haemopoieses and Haemopoietic Cell Migration

Abstract

α1,3 fucosylation is crucial in the formation of functional ligands for interaction with their corresponding selectin(s). These interactions regulate leukocyte migration and normal haemopoiesis. In mice, there are only three known α1,3 fucosyltransferases - Fut4, Fut7, and Fut9. This thesis describes the development of a novel mouse model with absence of all three α1,3 fucosyltransferases. This novel mouse model enabled a comprehensive study of the functions of these enzymes in regulating haemopoiesis. In mice that are deficient in Fut7, the lack of fucosylation of their selectin ligands led to increased granulopoiesis both in granulocytic progenitor cells and mature granulocytes. Bone marrow transplantation experiments demonstrated that this was a “cell intrinsic” property of granulocytic cells. The importance of Fut7 was also found to further extend into the regulation of erythroid differentiation and B lymphocyte maturation. Fucosyltransferase 9 played a limited role in leukocyte selectin mediated adhesion. This thesis demonstrated that the loss of Fut9 function by itself, or jointly with Fut4 and Fut7, did not have any additional impact on leukocyte migration and haemopoiesis. The work as outlined in this thesis contributes to the growing evidence that regulation of haemopoietic cell migration and haemopoiesis could be achieved through specific loss of functional adhesion ligands. The knowledge thus gained in the understanding of selectin-ligand interactions could be exploited in future research of therapeutic agents for treatment of haematological disorders.