The Magnificent Seventh

Important publications describing the effects of cytokines in the nervous system are demanding increasing amounts of our attention these days. Consider, for example, the chemotactic cytokines or chemokines. These small proteins have been extensively studied because of their importance in regulating leukocyte migration and inflammation. Approximately 50 different chemokines have been shown to exist in higher vertebrates. These can be organized into four subfamilies based on structural considerations and, as far as we know, all their effects are transduced by a family of G protein coupled receptors (GPCRs). In most instances, chemokines are not expressed at high concentrations, their expression being upregulated in association with an innate immune or inflammatory response. However, one chemokine does not fit this general description. Stromal cell-derived factor-1 (SDF-1, also called CXCL12) and its receptor CXCR4 are constitutively expressed at high levels in many tissues, including the nervous system (Li and Ransohoff 2008). Evolutionary considerations have indicated that CXCL12 is the most ancient chemokine and that it existed in animals prior to the development of a sophisticated immune system, suggesting that the original function of chemokine signaling had nothing to do with immunity (Huising et al., 2003). The ancient function of CXCL12/CXCR4 signaling appears to involve regulating the migration and development of the stem cells that generate nearly every tissue (Miller et al., 2008). Both CXCL12 and CXCR4 are highly expressed in the developing embryo, their distribution changing rapidly over time in association with the development of different structures. The overall importance of CXCR4 signaling during development has become abundantly clear from examination of CXCR4 knockout mice, which exhibit numerous phenotypes relating to the formation of nearly every tissue (Li and Ransohoff 2008). CXCR4 signaling regulates the development of many structures in the brain and peripheral nervous system, including parts of the cerebellum, cortex, and hippocampus and the dorsal root and sympathetic ganglia. Regulation of stem cell function by CXCR4 signaling continues in adult structures such as the bone marrow and the neurogenic niches of the brain. Although there is a great deal of data clearly demonstrating the importance of CXCR4 signaling in the directed migration of stem cell populations in the developing nervous system, details as to how this is actually accomplished remain to be elucidated. How exactly are gradients of CXCL12 established and how is the chemokine concentration in the local stem cell microenviroment precisely regulated? Now two extensive papers published in this issue of Neuron (Sánchez-Alcañiz et al., 2011; Wang et al., 2011) reveal important details about thesemechanisms and, specifically, how they help to explain the manner in which interneurons migrate into the developing cortex. The insights provided by these papers come from consideration of the properties of a recently described chemokine receptor known as CXCR7. CXCR7 is a member of a particular subgroup of chemokine receptors, which also include DARC, D6, and CCXCKR, whose properties are somewhat unusual for GPCRs because, even though they bind chemokines, they don’t actually activate G proteins (Graham 2009). An examination