CXCR4 is a G-protein coupled serpentine receptor for the CXC chemokine, CXCL12. CXCR4 and CXCL12 are expressed by cells of multiple lineages in the immune system and by many other tissues. Genetic studies have revealed essential roles of CXCR4 signaling in the development of many organs, notably the hematopoietic and central nervous systems. In both organ systems, CXCR4 signaling has been shown to trigger cell proliferation, to enhance cell survival, and to induce chemotaxis towards focal sources of CXCL12 ligand. However, the molecular mechanisms underlying the transduction of these CXCR4-mediated cellular responses remain obscure, and thus it remains unclear whether the interpretation of CXCR4 signaling by neural and hematopoietic cells involves common or divergent biochemical pathways. In addition, since mice lacking CXCR4 function die perinatally, the later physiological roles of CXCR4 remain poorly understood.
The primary goal of this proposed project is to elucidate the physiological function of CXCR4 in the immune and nervous systems, its potential pathogenic role in neuroinflammation, and the precise biological effects contributed by different signaling pathways downstream of the ligand-activated CXCR4. Toward this goal, we have generated mouse strains carrying CXCR4 gene mutations that can be deleted conditionally in specific tissues and under precise temporal control, and additional strains that are mutated in sequences encoding conserved signaling domains.
We plan to use both biochemical and cellular assays to characterize the physiological defects evident in both the hematopoietic and neural cells, in these selective CXCR4 mutant animals. These studies will permit identification of fundamentally conserved CXCR4 mediated signaling pathways shared by both the immune and nervous systems. Furthermore, using a mouse model for neuron injury and nervous degeneration, we will also investigate the pathogenic role of CXCR4 signalling in linking inflammatory responses to neuronal degeneration. Results gained from our studies could facilitate the development of new therapeutic strategies in immune and neurological disorders.