P6 - Novel functions of polysialic acid in kidney and immune cell development

The aim of this proposal is to unravel the role of polysialic acid (polySia) in the development of hematopoietic stem cells (HSC), hematopoiesis, and the maintenance of immune homeostasis. In the first funding period, we identified the chemokine CXCL12 as novel polySia binding protein. Initial analysis of mice lacking the polysialyltransferase ST8Sia4 revealed phenotypic alterations that are reminiscent to changes seen in animals with defects in the CXCR4/CXCL12 signaling axis, including altered HSC and immune homeostasis and signs for the development of the autoimmune disease Lupus nephritis in aged mice. In the next funding period, we will study structure-function relationships of CXCL12 to define, in close collaboration with project P8, key residues involved in polySia binding. To understand how polysialylation contributes to HSC development, we will extend our analyses in constitutive St8sia4 knockout mice and perform functional assays with isolated primary cells. Finally, we will complement efforts of projects P2 and P10 in dissecting the impact of ST8Sia4-deficiency on autoimmunity by generating B-cell specific St8Sia4 knockout mice. A specific focus will be set on the role of B-cell polysialylation for humoral immune response and the development of Lupus nephritis. Besides tight interactions with P2, P8 and P10, we will closely collaborate with P1, P5 and P9, and will get support from P3 and P7.