Regional and cellular localization of the CXCl12/SDF‐1 chemokine receptor CXCR7 in the developing and adult rat brain

Schönemeier, Bastian; Kolodziej, Angela; Schulz, Stefan; Jacobs, Stefan; Hoellt, Volker; Stumm, Ralf

doi:10.1002/cne.21780

Cited by 127 publications

(125 citation statements)

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“…While CXCR4 is reported to be more important during brain development, especially in migration and survival of neuronal and oligodendroglial precursor cells (28), CXCR7 is induced during maturation of glial cells (15), and is the predominant receptor for CXCL12 in the adult rodent brain (13). This seems to be reproduced during glioblastoma pathogenesis where glioblastoma stem-like cells show high CXCR4 and low CXCR7 levels and more mature glioblastoma cells switch to a predominant CXCR7 expression (16).…”

Section: Discussionmentioning

confidence: 99%

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CXCL12 mediates apoptosis resistance in rat C6 glioma cells

2012

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Abstract. The chemokine CXCL12/stromal cell-derived factor-1 (SDF-1) and its receptor CXCR4 regulate migration and patterning processes during brain development, but also contribute to proliferation and expansion of gliomas, the most malignant brain tumors. Recently, a previous orphan-receptor CXCR7/RDC-1 was discovered to be a second receptor for CXCL12. CXCR7 has been detected in normal brain parenchyma, but in particular in human brain tumors. However, little is known about the functional relevance of CXCR7. Since the well-characterized rat C6 glioma cell line is commonly used as a glioma model in vitro and in vivo, we investigated the expression, regulation and function of CXCL12 and its receptors in these tumor cells. Whereas CXCL12 and CXCR7 were transcribed at notable levels, CXCR4 was quite low. By sublethal doses of temozolomide, an alkylating drug commonly used in adjuvant glioma therapy, transcription of CXCL12 and its receptors were significantly induced. Decreased proliferation resulting from this sublethal treatment with temozolomide could be completely restored to normal proliferation rates by simultaneous stimulation with CXCL12. Similarly, CXCL12 protected C6 cells from apoptosis under treatment with higher temozolomide doses. Thus, the CXCL12-CXCR7 axis promotes glioma progression, and the rat C6 glioma cell line may be a useful model to further investigate these mechanisms in vitro and in vivo.

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Section: Discussionmentioning

confidence: 99%

“…In the CNS, CXCR7 can be found in the developing and adult rat brain (13), in primary rat astrocytes and Schwann cells (14), and it is upregulated in vivo and in vitro during maturation of oligodendrocytes (15). In human glioblastomas CXCR7 is located on tumor-associated capillaries and on the mass of tumor cells (16).…”

Section: Introductionmentioning

confidence: 99%

CXCL12 mediates apoptosis resistance in rat C6 glioma cells

2012

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“…CXCL12 was originally identified as a bone marrow stromal cell-derived chemoattractant and proliferative factor for B-cell precursors and binds two receptors, CXCR4, which couples to the G i family of signal transducers (9), and CXCR7, whose signaling capacity is unclear and may function predominantly to regulate CXCR4 activation via sequestration of CXCL12 (10). Transcripts for CXCL12, CXCR4, and CXCR7 are detected in the CNS of rodent embryos (11,12), where these molecules function to promote proliferation and migration of neural precursors (13,14). In the mature CNS, both CXCR4 and CXCR7 are expressed by subpopulations of neurons, whereas CXCR7 is additionally expressed by the endothelium and CXCR4 by neural stem cells (NSCs) and mediates their homing to damaged areas within the CNS (12, 15, 16).…”

mentioning

confidence: 99%

“…Transcripts for CXCL12, CXCR4, and CXCR7 are detected in the CNS of rodent embryos (11,12), where these molecules function to promote proliferation and migration of neural precursors (13,14). In the mature CNS, both CXCR4 and CXCR7 are expressed by subpopulations of neurons, whereas CXCR7 is additionally expressed by the endothelium and CXCR4 by neural stem cells (NSCs) and mediates their homing to damaged areas within the CNS (12,15,16). Although several in vitro studies suggest possible roles for CXCL12 and CXCR4 in the migration and maturation of OPCs (17)(18)(19), these questions have not been studied in vivo.…”

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confidence: 99%

CXCR4 promotes differentiation of oligodendrocyte progenitors and remyelination

Patel

McCandless

Dorsey

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

209

206

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Multiple sclerosis is a neurodegenerative disease characterized by episodes of autoimmune attack of oligodendrocytes leading to demyelination and progressive functional deficits. Because many patients exhibit functional recovery in between demyelinating episodes, understanding mechanisms responsible for repair of damaged myelin is critical for developing therapies that promote remyelination and prevent disease progression. The chemokine CXCL12 is a developmental molecule known to orchestrate the migration, proliferation, and differentiation of neuronal precursor cells within the developing CNS. Although studies suggest a role for CXCL12 in oligodendroglia ontogeny in vitro, no studies have investigated the role of CXCL12 in remyelination in vivo in the adult CNS. Using an experimental murine model of demyelination mediated by the copper chelator cuprizone, we evaluated the expression of CXCL12 and its receptor, CXCR4, within the demyelinating and remyelinating corpus callosum (CC). CXCL12 was significantly up-regulated within activated astrocytes and microglia in the CC during demyelination, as were numbers of CXCR4+ NG2+ oligodendrocyte precursor cells (OPCs). Loss of CXCR4 signaling via either pharmacological blockade or in vivo RNA silencing led to decreased OPCs maturation and failure to remyelinate. These data indicate that CXCR4 activation, by promoting the differentiation of OPCs into oligodendrocytes, is critical for remyelination of the injured adult CNS.M ultiple sclerosis (MS), a progressive, neurodegenerative disease of the CNS, occurs most often in a relapsing/remitting form, in which a period of demyelination is followed by a period of functional recovery (1). The recovery stage involves remyelination via the migration and maturation of oligodendrocyte precursor cells (OPCs) (2). However, as the disease progresses, remyelination fails with continuous loss of function (3). Possible explanations for remyelination failure of intact axons include defects in OPC recruitment to the site of demyelination or in OPC differentiation into myelinating oligodendrocytes. Although studies indicate that both aspects of OPC biology are altered in MS (4, 5), the molecular mechanisms that orchestrate these processes within the adult CNS are incompletely understood.Studies in mice indicate that neural precursors that give rise to cells of oligodendrocytes lineage can be identified within the ventral half of the ventricular zones of all CNS regions by embryonic days 12-14 (E12-E14) via their expression of NG2 chondroitin sulfate proteoglycan (6). In the final stage of oligodendrocyte differentiation, which occurs primarily during the postnatal period (P4-P12), OPCs begin to express mature markers of oligodendrocytes including 2′3′-cyclic nucleotide phosphohydrolase (CNPase), myelin basic protein (MBP), proteolipid protein (PLP) and myelin oligodendrocyte glycoprotein (MOG). Similar events occur during remyelination; NG2+ OPCs proliferate within subventricular zones, migrate to areas of demyelination, and differentiate ...

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“…CXCR7 knockout mice have demonstrated cardiac valve malformation or enlarged hearts (Leung et al, 2007;Gerrits et al, 2008), and no brain defects were observed in these animals. CXCR7 mRNA expression was considerably increased in the granular layer and in the CA3 pyramidal cell layer in the postnatal rat brain (Schönemeier et al, 2008). Thus, further studies are needed to explore whether CXCR7 is involved with mossy fiber sprouting during spatial learning and memory.…”

Section: Discussionmentioning

confidence: 99%

Sprouting of Nervous Fibers and Upregulation of C‐X‐C Chemokine Receptor Type 4 Expression in Hippocampal Formation of Rats with Enhanced Spatial Learning and Memory

Bao-gui

Pan

et al. 2011

The Anatomical Record

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Hippocampal mossy fiber sprouting following training in the Morris water maze (MWM) is associated with spatial learning, memory and neural plasticity. The C-X-C chemokine receptor type 4 (CXCR4) is the main receptor for stromal cell-derived factor-1 (SDF-1), which is a chemokine that can regulate axonal elongation. This study aimed to investigate the relationship between the morphological plasticity of hippocampal formation and CXCR4 expression. A model of spatial learning and memory was established in rats by training using the MWM. Mossy fiber sprouting in the striatum oriens of the CA3 area of the hippocampus was found in trained rats by Neo-Timm's method. As shown by immunohistochemistry, the CXCR4 immunopositive neurons were distributed in all layers and areas of hippocampal formation. There were no differences among groups regarding the distribution or shape of the immunopositive neurons. However, the immunoreactive staining intensity was increased in trained rats as compared with the control rats. Both CXCR4 gene transcription and translation were significantly upregulated in the trained group as compared with the control group (P < 0.01). Morphological plasticity in the form of axonal sprouting in the hippocampal formation can be induced by enhanced spatial learning and memory activity, and CXCR4 mRNA and protein expression is upregulated, indicating a positive correlation between CXCR4 expression and axonal sprouting. Anat Rec, 295:121-126, 2012. V V C 2011 Wiley Periodicals, Inc.

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Regional and cellular localization of the CXCl12/SDF‐1 chemokine receptor CXCR7 in the developing and adult rat brain

Cited by 127 publications

References 61 publications

CXCL12 mediates apoptosis resistance in rat C6 glioma cells

CXCL12 mediates apoptosis resistance in rat C6 glioma cells

CXCR4 promotes differentiation of oligodendrocyte progenitors and remyelination

Sprouting of Nervous Fibers and Upregulation of C‐X‐C Chemokine Receptor Type 4 Expression in Hippocampal Formation of Rats with Enhanced Spatial Learning and Memory

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