As mentioned previously, CXCR4 is expressed in glial cells (astrocytes and microglia but not oligodendrocytes) as well as in neurons. In the adult brain, neuronal expression of CXCR4 is localized to cerebral cortex, caudate putamen, globus pallidus, substantia innominata, supraoptic and paraventricular hypothalamic nuclei, ventromedial thalamic nucleus, dentate gyrus, cerebellum, ento-rhinal cortex, and substantia nigra. Astrocytes represent the major cellular source of the CXCR4 ligand CXCL12 in the brain. In vitro studies have demonstrated that CXCL12 is a potent chemoattractant for several types of neural cells, including neuronal precursor cells from the external germinal layer, cortical neuronal progenitors, cerebellar granule neurons, and dentate gyrus granular neurons (37,38). Disruption of either CXCR4 or CXCL12 in gene-targeted mice gives similar but not identical pathophysiologic outcomes; mice died soon after birth and exhibited severe abnormalities in cerebellar development (39). Defects included distorted laminar structure and abnormal migration of cells from the proliferative external granule cells in the developing cerebellum, with establishment of proliferating aggregates and absence of foliation. CXCR4-deficient mice also showed abnormal development of hippocampal dentate gyrus, which compared with wild-type mice appeared small and immature. This abnormality was attributed to deficits in granule cell migration and a reduction in the number of dividing neuronal precursors. In addition, the distribution of interneurons in the neocortex of CXCR4- and CXCL12-deficient mice was severely perturbed. Additionally, it is critical for normal brain and spinal cord development to receive CXCL12/CXCR4 signals for axonal responsiveness to known guidance cues (40,41).
CXCR4 actions, however, go beyond physiologic cellular positioning of neuron progenitors in the developing CNS (42). Further, activation of CXCR4 in astrocytes causes release of TNF-a and subsequent downmodulation of critically important astrocytic transporters (responsible for removing extracellular glutamate) and promoting neuronal apoptosis via excitotoxicity. During CNS inflammation, microglia enhance this neurotoxic mechanism by producing TNF-a and triggering release of glutamate (43). This complex signaling pathway by which CXCL12 evokes glutamate release and modulation of neuronal function has been termed the glutamate-chemokine connection (43,44). Another important role of CXCR4 is highlighted by various in vivo studies showing that blockade of CXCR4 by antibodies or small antagonists inhibits tumor cell migration (45). Therefore in cancer biology, CXCR4 is envisioned as a target for novel strategies in the treatment of various malignancies, including gliomas and medulloblastomas (46). Such new approaches include blockade of mechanisms involved in tumor cell growth and metastatic spreading (45,47-49). Another important role is evident by the finding of Cxcr4 mutations that are associated with a rare inherited human immunologic disorder named WHIM (for warts, hypogammaglobulinemia, infections, and myelokathexis) (50). This human immunodeficiency appears to rise from aberrant signaling of the mutant receptor and is clinically manifested by a prolonged retention of neutrophils in the bone marrow compartment, chronic leucopenia, and extensive human papil-lomavirus infection (50-52). In addition to their instrumental role in architectural organization, brain morphogenesis, and axonal guidance, CXCL12/CXCR4 is also involved in neuronal function, tumor development, and immune and stem cell trafficking (53,54).
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