Abstract

The alternative SDF-1 (stromal cell derived factor-1) receptor, CXCR7, has been suggested to act as either a scavenger of extracellular SDF-1 or a modulator of the primary SDF-1 receptor, CXCR4. CXCR7, however, also directly affects the function of various tumor-cell types. Here, we demonstrate that CXCR7 is an active component of SDF-1 signalling in astrocytes and Schwann cells. Cultured cortical astrocytes and peripheral nerve Schwann cells exhibit comparable total and cell-surface levels of expression of both SDF-1 receptors. Stimulation of astrocytes with SDF-1 resulted in the temporary activation of Erk1/2, Akt and PKCzeta/lambda, but not p38 and PKCalpha/beta. Schwann cells showed SDF-1-induced activation of Erk1/2, Akt and p38, but not PKCalpha/beta and PKCzeta/lambda. The respective signalling pattern remained fully inducible in astrocytes from CXCR4-deficient mice, but was abrogated following depletion of astrocytic CXCR7 by RNAi. In Schwann cells, RNAi-mediated depletion of either CXCR4 or CXCR7 silenced SDF-1 signalling. The findings of the astrocytic receptor-depletion experiments were reproduced by CXCR7 antagonist CCX754, but not by CXCR4 antagonist AMD3100, both of which abolished astrocytic SDF-1 signalling. Further underlining the functional importance of CXCR7 signalling in glial cells, we show that the mitogenic effects of SDF-1 on both glial cell types are impaired upon depleting CXCR7.

Highlights

  • The CXC chemokine SDF-1 was originally isolated as a pre-B-cell growth-stimulating factor and was subsequently shown to regulate trafficking, transendothelial migration, proliferation and differentiation of hematopoietic cells (Broxmeyer, 2008)

  • We demonstrate that CXCR7 is an active component of SDF-1 signalling in astrocytes and Schwann cells

  • Stimulation of astrocytes with SDF-1 resulted in the temporary activation of extracellular-signal-regulated kinases 1 and 2 (Erk1/2), Akt and protein kinase C (PKC) /, but not p38 and PKC /

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Summary

Introduction

The CXC chemokine SDF-1 (stromal cell derived factor-1; known as CXCL12) was originally isolated as a pre-B-cell growth-stimulating factor and was subsequently shown to regulate trafficking, transendothelial migration, proliferation and differentiation of hematopoietic cells (Broxmeyer, 2008). In the adult nervous system, expression of SDF-1 and its receptor, CXCR4, persists in astrocytes, microglial cells, Schwann cells, distinct neuronal populations and endothelial cells (Li and Ransohoff, 2008), modulating neurotransmitter release from neurons and glia as well as hormone secretion from neuroendocrine cells (Bezzi et al, 2001; Barbieri et al, 2007; Lazarini et al, 2003; Rostène et al, 2007). CXCR4 controls growth, migration and invasion of various tumours, including glioma and astrocytoma (Balkwill, 2004)

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