Examining a Receptor Used in Both Immune and Nervous System Development

Yong-Rui Zou, Ph.D.

Columbia University

Funded in January, 2003: $300000 for 5 years
LAY SUMMARY . ABSTRACT . SELECTED PUBLICATIONS .

LAY SUMMARY

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Examining a Receptor Used in Both Immune and Nervous System Development

The Columbia researchers will investigate in animals how a specific receptor, which resides on the surface of both immune and nerve cells, signals normally during cell development and how it malfunctions and leads to abnormal cell development.

The receptor is called “CXCR4.”  It is involved in both the developing immune and central nervous systems and is a critical factor in the normal development of the body’s organs.  Defects in the receptor’s signaling processes, however, can alter cell development in both the immune and nervous systems. Specifically, deficient signaling can alter the development of white blood cells (lymphocytes) as they grow in bone marrow.  Overactive receptor signaling can induce the death of neurons, astrocytes (which contribute to the formation of the boundaries of the blood-brain-barrier) and microglia (immune cells that reside in the brain).  Still unknown are the key cellular and molecular determinants of normal and impaired CXCR4 signaling.

The Columbia researchers will use both genetic and cell biology methods in mice to determine the role of CXCR4 in central nervous system organization and immune function.  The investigators will examine whether the receptor’s signaling pathways play different roles in cell death, lymphocyte (white blood cell) development, and guidance of motor nerve axons (those involved in movement).  Understanding CXCR4 signaling in immune and nerve cells is anticipated to have direct clinical relevance, helping to determine how this fundamental signaling pathway is modified to suit the specific functions performed by cells in both systems.

ABSTRACT

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Examining a Receptor Used in Both Immune and Nervous System Development

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.

SELECTED PUBLICATIONS

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Lieberam I., Agalliu D., Nagasawa T., and Jessell T.M.  A Cxcl12-CXCR4 chemokine signaling pathway defines the initial trajectory of mammalian motor axons.  Neuron. 2005 Sep 1;47(5):667-79.

Nie Y., Waite J., Brewer F., Sunshine M.J., Littman D.R., and Zou Y.R.   The role of CXCR4 in maintaining peripheral B cell compartments and humoral immunity.   J Exp Med. 2004 Nov 1;200(9):1145-56.