Genetic mechanisms which control hematopoietic cell migration

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Migration of hematopoietic stem cells (HSC) to appropriate microenvironments within the bone marrow is critical to the success of bone marrow transplantation (BMT). Homing of HSC and hematopoietic progenitors both during BMT and during normal homeostasis is controlled in part by selectins, a family of 3 adhesion molecules which are also critical for mature leukocyte recruitment in settings of inflammation, metastasis, and lymphocyte recirculation. In particular, homing of HSC to bone marrow relies on expression of E-selectin and/or P-selectin on bone marrow endothelial cells as an obligate step in entering specialized niches within the marrow. The physiologic ligands for selectins are carbohydrates, and these glycans are formed by the sequential action of a number of glycosyltransferases. The terminal, regulated step in biosynthesis of all selectin ligands is mediated by the 11,3 fucosyltransferase FucT-VII, which adds a fucose residue 11,3 to a sialylated lactosamine precursor to form structures of the type (Neu5Ac(12-3)Gal(21-4)[Fuc(11-3)]GlcNAc-R). These structures constitute essential elements of ligands for selectins. Mice deficient in FucT-VII exhibit neutrophilia, altered hematopoiesis, and severe defects in immune and inflammatory responses, reflecting the broadly critical importance of this enzyme and the diverse set of processes in which selectins participate. The pattern of expression of FucT-VII and the lack of any phenotype unrelated to selectin ligands in FucT-VII null mice suggest that this enzyme is dedicated to function in selectin ligand biosynthesis. Because post-translational modifications such as phosphorylation play no role in the regulation of glycosyltransferase enzymatic activity, the enzymatic activity of glycosyltransferases is controlled primarily, if not exclusively, at the level of gene expression. However, despite the well documented critical importance of FucT-VII for effective hematopoiesis, inflammation and immunity, surprisingly little is known about how expression of the fut7 gene encoding this key enzyme is regulated in different hematopoietic lineages. In this application, we propose experiments to comprehensively identify cis-acting genetic elements which control fut7 gene expression, and to develop a transgenic, genetic complementation gain-of-function approach for testing the functionality of these elements in vivo. These results will provide a solid, long term foundation to unravel transcriptional, genetic, and epigenetic mechanisms which control fut7 gene expression. PUBLIC HEALTH RELEVANCE During a bone marrow transplant, specialized blood cells called stem cells travel through the bloodstream and enter the bone marrow in response to chemical signals from the tissues. This process involves specific sugars on the surface of these stem cells which bind to specific receptors on the blood vessel wall in the bone marrow. Understanding how expression of these sugars is regulated is therefore of high importance to understanding how bone marrow transplantation works as well as related processes.