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• W2113306635 abstract "Chemokine signaling is a key regulator of stem cell migration and development. However, how chemokine gradients are generated for signaling purposes is not understood. Sánchez-Alcañiz et al. and Wang et al. in this issue of Neuron now describe how the discovery of a new chemokine receptor called CXCR7 helps to provide answers to this question. Chemokine signaling is a key regulator of stem cell migration and development. However, how chemokine gradients are generated for signaling purposes is not understood. Sánchez-Alcañiz et al. and Wang et al. in this issue of Neuron now describe how the discovery of a new chemokine receptor called CXCR7 helps to provide answers to this question. 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, 2008Li M. Ransohoff R.M. Prog. Neurobiol. 2008; 84: 116-131Crossref PubMed Scopus (264) Google Scholar). 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., 2003Huising M.O. Stet R.J. Kruiswijk C.P. Savelkoul H.F. Lidy Verburg-van Kemenade B.M. Trends Immunol. 2003; 24: 307-313PubMed Google Scholar). 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., 2008Miller R.J. Banisadr G. Bhattacharyya B.J. J. Neuroimmunol. 2008; 198: 31-38Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar). 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, 2008Li M. Ransohoff R.M. Prog. Neurobiol. 2008; 84: 116-131Crossref PubMed Scopus (264) Google Scholar). 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., 2011Sánchez-Alcañiz J.A. Haege S. Mueller W. Pia R. Mackay F. Schulz S. Lopez-Bendito G. Stumm R. Marin O. Neuron. 2011; 69 (this issue): 77-90Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar, Wang et al., 2011Wang Y. Li G. Stanco A. Long J.E. Crawford D. Potter G.B. Pleasure S.J. Behrens T. Rubenstein J.L.R. Neuron. 2011; 69 (this issue): 61-76Abstract Full Text Full Text PDF PubMed Scopus (201) Google Scholar) reveal important details about these mechanisms 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, 2009Graham G.J. Eur. J. Immunol. 2009; 39: 342-351Crossref PubMed Scopus (105) Google Scholar). An examination of their sequences reveals that these receptors don't contain the amino acid motif that has been typically associated with the activation of G proteins by chemokine receptors. So, what do these proteins do? If they don't activate G proteins are they capable of alternative types of signaling? Nowadays the repertoire of known signaling pathways associated with GPCRs is truly immense and so non-G-protein-related functions can certainly be envisaged (Rajagopal et al., 2010aRajagopal S. Rajagopal K. Lefkowitz R.J. Nat. Rev. Drug Discov. 2010; 9: 373-386Crossref PubMed Scopus (624) Google Scholar). Moreover, what exactly are their biological functions? One idea is that these molecules function as “decoy” receptors. That is to say they can bind chemokines and remove them from the external environment through receptor-mediated endocytosis, a property commonly associated with GPCRs. Once internalized by a decoy receptor, a particular chemokine may be degraded or even perhaps rereleased intact from another part of the cell—a process known as transcytosis. Previously, receptors like DARC and D6 have been shown to bind and internalize numerous chemokines—but not CXCL12. However, the great interest in CXCR7 is that it does bind CXCL12 with very high affinity. In fact, apart from the possibility that it can also bind CXCL11, CXCL12 appears to be its only ligand. So, does CXCR7 cooperate with CXCR4 in mediating CXCL12 signaling and, if so, how? One suggestion is that CXCR7 and CXCR4 form heterodimers modulating CXCR4 signaling which normally involves the activation of Gαi/o (Levoye et al., 2009Levoye A. Balabanian K. Baleux F. Bachelerie F. Lagane B. Blood. 2009; 113: 6085-6093Crossref PubMed Scopus (440) Google Scholar) Another suggestion is that the two receptors signal through the activation of different pathway, which might then interact intracellularly at some level. Perhaps the major function of CXCR7 is indeed the removal of CXCL12 from the local environment so that signaling via the CXCR4 receptor can be more precisely defined. Several papers have demonstrated that CXCR7 can readily interact with the intracellular scaffold protein β-arrestin 2, which is associated with receptor endocytosis (Rajagopal et al., 2010bRajagopal S. Kim J. Ahn S. Craig S. Lam C.M. Gerard N.P. Gerard C. Lefkowitz R.J. Proc. Natl. Acad. Sci. USA. 2010; 107: 628-632Crossref PubMed Scopus (396) Google Scholar). Indeed, it has been observed that CXCR7 is normally localized intracellularly and that it rapidly shuttles between the cell surface and intracellular compartments (Luker et al., 2010Luker K.E. Steele J.M. Mihalko L.A. Ray P. Luker G.D. Oncogene. 2010; 29: 4599-4610Crossref PubMed Scopus (160) Google Scholar). Over the years the group of investigators represented by Wang et al., 2011Wang Y. Li G. Stanco A. Long J.E. Crawford D. Potter G.B. Pleasure S.J. Behrens T. Rubenstein J.L.R. Neuron. 2011; 69 (this issue): 61-76Abstract Full Text Full Text PDF PubMed Scopus (201) Google Scholar have carefully defined the mechanisms by which the different populations of cortical GABAergic interneurons develop from their germinal zones. For example, progenitor cells localized in the medial ganglionic eminence (MGE) express a variety of transcription factors that can be used to trace their migration and development. Deletion of the transcription factor Lhx6 from the pool of MGE progenitors substantially disrupts their normal path of migration into the cortex. An important question therefore is what are the genes downstream of such transcription factors that mediate the actual mechanics of interneuron migration? Previous publications have demonstrated that Lhx6 helps to control the expression of CXCR4 by migrating progenitors and that CXCR4 and Lhx6 knockout mice show similar defects in interneuron migration (Zhao et al., 2008Zhao Y. Flandin P. Long J.E. Cuesta M.D. Westphal H. Rubenstein J.L. J. Comp. Neurol. 2008; 510: 79-99Crossref PubMed Scopus (143) Google Scholar). At the time when interneuron progenitors migrate from the MGE, CXCL12 is expressed in two locales in the developing cortex .The chemokine is strongly expressed in the meninges and also in a deeper location that corresponds to the subventricular zone (SVZ)/intermediate zone (IZ).CXCR4-expressing progenitors in the MGE form migratory streams attracted by these sources of CXCL12 and normally populate the marginal zone (MZ) and SVZ (Tiveron et al., 2006Tiveron M.C. Rossel M. Moepps B. Zhang Y.L. Seidenfaden R. Favor J. König N. Cremer H. J. Neurosci. 2006; 26: 13273-13278Crossref PubMed Scopus (148) Google Scholar). Disruption of CXCR4 signaling causes a failure of migrating interneurons to populate their normal destinations and results in overpopulation of the cortical plate (CP) region from which they are normally excluded. Early studies on the phenotypes of CXCR7 knockout mice did not report any abnormalities in nervous system development. However, the abundant expression of CXCR7 in the developing brain suggested that phenotypes might well be observed on closer inspection (Schönemeier et al., 2008Schönemeier B. Kolodziej A. Schulz S. Jacobs S. Hoellt V. Stumm R. J. Comp. Neurol. 2008; 510: 207-220Crossref PubMed Scopus (112) Google Scholar). Indeed, the papers by Wang et al., 2011Wang Y. Li G. Stanco A. Long J.E. Crawford D. Potter G.B. Pleasure S.J. Behrens T. Rubenstein J.L.R. Neuron. 2011; 69 (this issue): 61-76Abstract Full Text Full Text PDF PubMed Scopus (201) Google Scholar and Sánchez-Alcañiz et al., 2011Sánchez-Alcañiz J.A. Haege S. Mueller W. Pia R. Mackay F. Schulz S. Lopez-Bendito G. Stumm R. Marin O. Neuron. 2011; 69 (this issue): 77-90Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar both demonstrate that not only is CXCR7 coexpressed with CXCR4 in migrating MGE progenitors but also that deletion of CXCR7 produces a phenotype that appears virtually identical to that observed in CXCR4 deficient mice. In both CXCR4 and CXCR7 mutants, migrating Lhx6-expressing progenitors exhibit reduced tangential and increased radial migration resulting in their enhanced positioning in the CP at the expense of the MZ or SVZ. Such observations suggest that CXCR4/CXCR7 may cooperate in regulating interneuron migration—but how? Wang et al., 2011Wang Y. Li G. Stanco A. Long J.E. Crawford D. Potter G.B. Pleasure S.J. Behrens T. Rubenstein J.L.R. Neuron. 2011; 69 (this issue): 61-76Abstract Full Text Full Text PDF PubMed Scopus (201) Google Scholar make several important observations that help in answering this question. In one experiment, they ectopically expressed CXCL12 in the cortex of control or mutant mice. In wild-type mice Lhx6-expressing progenitors migrated toward this ectopic source. On the other hand, no progenitor migration was observed in either CXCR7 or CXCR4 mutant mice, indicating that expression of both of these receptors is equally important for directed migration to occur. However, when the authors examined the migratory properties of individual mutant progenitors in cortical slices, they found that CXCR4 mutant cells were more motile and CXCR7 mutant cells were less motile than wild-type cells. Hence the authors conclude that the two receptors must have different, but interdependent, signaling consequences in directing progenitor migration. Further experiments indicated what these signaling pathways might be. It is well known that CXCR4 receptors signal via the pertussis toxin (PTX)-sensitive G proteins Gαi/o. Using a genetic manipulation for expressing PTX in migrating interneurons, Wang et al., 2011Wang Y. Li G. Stanco A. Long J.E. Crawford D. Potter G.B. Pleasure S.J. Behrens T. Rubenstein J.L.R. Neuron. 2011; 69 (this issue): 61-76Abstract Full Text Full Text PDF PubMed Scopus (201) Google Scholar demonstrated that inhibition of Gαi/o in these cells produces the same phenotype as inhibiting CXCR4, further illustrating the importance of CXCR4 signaling. CXCR7 receptors can't activate Gαi/o but are able to signal via β-arrestin. As β-arrestin can act as a scaffold protein for intermediates of the MAP kinase pathway, this could represent a signaling option for these receptors. Indeed, Wang et al., 2011Wang Y. Li G. Stanco A. Long J.E. Crawford D. Potter G.B. Pleasure S.J. Behrens T. Rubenstein J.L.R. Neuron. 2011; 69 (this issue): 61-76Abstract Full Text Full Text PDF PubMed Scopus (201) Google Scholar do demonstrate that CXCR7 can activate the MAP kinase pathway in migrating progenitors. The mechanism of CXCR4/CXCR7 cooperation is beautifully illuminated by the studies of Sánchez-Alcañiz et al., 2011Sánchez-Alcañiz J.A. Haege S. Mueller W. Pia R. Mackay F. Schulz S. Lopez-Bendito G. Stumm R. Marin O. Neuron. 2011; 69 (this issue): 77-90Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar. These authors also conclude that migrating interneurons express both CXCR4 and CXCR7 and that migration is dependent on both receptors. However, they make one further absolutely key observation. They show that migrating cells that lack CXCR7 in CXCR7 mutant mice also lack CXCR4 protein expression (the mRNA is still expressed).Why should CXCR4 disappear if CXCR7 is removed? Sánchez-Alcañiz et al., 2011Sánchez-Alcañiz J.A. Haege S. Mueller W. Pia R. Mackay F. Schulz S. Lopez-Bendito G. Stumm R. Marin O. Neuron. 2011; 69 (this issue): 77-90Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar show, and Wang et al., 2011Wang Y. Li G. Stanco A. Long J.E. Crawford D. Potter G.B. Pleasure S.J. Behrens T. Rubenstein J.L.R. Neuron. 2011; 69 (this issue): 61-76Abstract Full Text Full Text PDF PubMed Scopus (201) Google Scholar also observe, that most of the CXCR7 in migrating interneurons is intracellular, something consistent with other papers in the literature. Sánchez-Alcañiz et al., 2011Sánchez-Alcañiz J.A. Haege S. Mueller W. Pia R. Mackay F. Schulz S. Lopez-Bendito G. Stumm R. Marin O. Neuron. 2011; 69 (this issue): 77-90Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar note that CXCR7 actively recycles between the membrane and the interior of the cell. It appears that CXCR7 is constantly involved in binding and internalizing CXCL12. Hence, as they predict, Sánchez-Alcañiz et al., 2011Sánchez-Alcañiz J.A. Haege S. Mueller W. Pia R. Mackay F. Schulz S. Lopez-Bendito G. Stumm R. Marin O. Neuron. 2011; 69 (this issue): 77-90Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar demonstrate that removal of CXCR7 produces a huge increase in the extracellular levels of CXCL12. Normally, when CXCL12 binds to CXCR4, in addition to G protein activation, it also produces receptor endocytosis and degradation. Hence, if the extracellular CXCL12 concentration is too high, it will trigger endocytosis and degradation of all of the CXCR4 in the cell. Viewed in this way, one can see that the important function for CXCR7 in these cells is to carefully titrate the concentration of CXCL12 in the local microenviroment so that just the right amount of signaling occurs. If CXCR7 disappears, then extracellular CXCL12 levels will be too high, overactivation of CXCR4 will occur and it will also disappear from the cell. Thus, removal of CXCR7 will result in the disappearance of CXCR4 and so this is why both kinds of mutant mice have the same phenotype—Q.E.D.! Both papers also demonstrate that CXCR7 is frequently expressed in the developing brain in the absence of CXCR4.The two sets of authors particularly note CXCR7 expression in immature projection neurons of the CP and in other areas that are typically avoided by migrating interneurons. This is also consistent with its proposed function as a decoy or scavenger receptor helping to shape gradients of CXCL12 that will determine paths for CXCR4-mediated chemotaxis. Clearly therefore, like all seasoned performers, CXCR7 is comfortable with a role either as a soloist or dancing a pas de deux with CXCR4. Overall, therefore, these two papers provide a detailed picture of how two chemokine receptors cooperate in enabling the successful migration of a specific group of neural progenitors in the developing brain. And, like all important investigations, they also raise numerous issues and questions. For example, what is the significance of CXCR7-induced MAP kinase activation or other types of cell signaling ? Is such signaling important in producing CXCR7-mediated effects in addition to its scavenging function? Wang et al., 2011Wang Y. Li G. Stanco A. Long J.E. Crawford D. Potter G.B. Pleasure S.J. Behrens T. Rubenstein J.L.R. Neuron. 2011; 69 (this issue): 61-76Abstract Full Text Full Text PDF PubMed Scopus (201) Google Scholar demonstrate that this type of signaling occurs, but how it influences the role of CXCR7 is unclear given the phenotype produced by PTX activation in migrating neurons. In addition, the expression of CXCR7 occurs in cells outside the developing embryo, including in cancer cells, which are often viewed as cells undergoing a dysregulated form of development. Given the important role of CXCR4 signaling in the spread of cancer metastases (Teicher and Fricker, 2010Teicher B.A. Fricker S.P. Clin. Cancer Res. 2010; 16: 2927-2931Crossref PubMed Scopus (890) Google Scholar), the functions of proteins like CXCR7 that can powerfully modify CXCR4 signaling are clearly of mechanistic and potentially therapeutic importance. Indeed, it is now clear that the discovery of CXCR7 has added an entirely new dimension to our understanding of how CXCR4 functions during development and beyond. Cxcr7 Controls Neuronal Migration by Regulating Chemokine ResponsivenessSánchez-Alcañiz et al.NeuronJanuary 13, 2011In BriefThe chemokine Cxcl12 binds Cxcr4 and Cxcr7 receptors to control cell migration in multiple biological contexts, including brain development, leukocyte trafficking, and tumorigenesis. Both receptors are expressed in the CNS, but how they cooperate during migration has not been elucidated. Here, we used the migration of cortical interneurons as a model to study this process. We found that Cxcr4 and Cxcr7 are coexpressed in migrating interneurons, and that Cxcr7 is essential for chemokine signaling. Full-Text PDF Open ArchiveCXCR4 and CXCR7 Have Distinct Functions in Regulating Interneuron MigrationWang et al.NeuronJanuary 13, 2011In BriefCXCL12/CXCR4 signaling is critical for cortical interneuron migration and their final laminar distribution. No information is yet available on CXCR7, a newly defined CXCL12 receptor. Here we demonstrated that CXCR7 regulated interneuron migration autonomously, as well as nonautonomously through its expression in immature projection neurons. Migrating cortical interneurons coexpressed Cxcr4 and Cxcr7, and Cxcr7–/– and Cxcr4–/– mutants had similar defects in interneuron positioning. Ectopic CXCL12 expression and pharmacological blockade of CXCR4 in Cxcr7–/– mutants showed that both receptors were essential for responding to CXCL12 during interneuron migration. Full-Text PDF Open Archive" @default.
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