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Disruption of Eph/ephrin signaling affects migration and proliferation in the adult subventricular zone

Abstract

The subventricular zone (SVZ) of the lateral ventricles, the largest remaining germinal zone of the adult mammalian brain, contains an extensive network of neuroblasts migrating rostrally to the olfactory bulb. Little is known about the endogenous proliferation signals for SVZ neural stem cells or guidance cues along the migration pathway. Here we show that the receptor tyrosine kinases EphB1–3 and EphA4 and their transmembrane ligands, ephrins-B2/3, are expressed by cells of the SVZ. Electron microscopy revealed ephrin-B ligands associated with SVZ astrocytes, which function as stem cells in this germinal zone. A three-day infusion of the ectodomain of either EphB2 or ephrin-B2 into the lateral ventricle disrupted migration of neuroblasts and increased cell proliferation. These results suggest that Eph/ephrin signaling is involved in the migration of neuroblasts in the adult SVZ and in either direct or indirect regulation of cell proliferation.

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Figure 1: Expression of EphB1–3 and EphA4 receptors in the SVZ of the lateral ventricle.
Figure 2: Expression of ephrin-B2 and B3 ligands in the SVZ of the lateral ventricle.
Figure 3: Infusion of ephrin-B2-Fc and EphB2-Fc into the lateral ventricle disrupts chain migration of SVZ neuroblasts.
Figure 4: Infusion of ephrin-B2-Fc and EphB2-Fc into the lateral ventricle results in increased cell proliferation within the SVZ.
Figure 5: Infusion of EphB2-Fc into the lateral ventricle increases the number of SVZ astrocytes (B cells) and reveals many B cells in contact with the ventricle.

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Acknowledgements

We acknowledge technical assistance from S. Haripal, M. Rutkowski, S. Loesener and D. Benavides. We thank M. Henkemeyer for EphB2lacZ/lacZ mice, and F. Helmbacher and P. Charney for an antibody to EphA4. We also thank L. Bianchi and members of the laboratory for comments on the manuscript. JCC thanks Al. Prochiantz for advice and laboratory space during a portion of this project. This work was supported by NIH grants to JCC and AAB and a Philippe Foundation Award to JCC.

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Correspondence to Joanne C. Conover.

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Conover, J., Doetsch, F., Garcia-Verdugo, JM. et al. Disruption of Eph/ephrin signaling affects migration and proliferation in the adult subventricular zone. Nat Neurosci 3, 1091–1097 (2000). https://doi.org/10.1038/80606

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