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First published online June 19, 2009
doi: 10.1242/10.1242/dev.034405


Development 136, 2467-2476 (2009)
Published by The Company of Biologists 2009


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Promotion of proliferation in the developing cerebral cortex by EphA4 forward signaling

Hilary A. North, Xiumei Zhao*, Sharon M. Kolk*,{dagger}, Meredith A. Clifford, Daniela M. Ziskind{ddagger} and Maria J. Donoghue§

Department of Biology and Interdisciplinary Program in Neuroscience, Georgetown University, 334 Reiss Science Building, Washington, DC 20057, USA.

§ Author for correspondence (e-mail: mjv23{at}georgetown.edu)

Accepted 5 May 2009

Eph receptors are widely expressed during cerebral cortical development, yet a role for Eph signaling in the generation of cells during corticogenesis has not been shown. Cortical progenitor cells selectively express one receptor, EphA4, and reducing EphA4 signaling in cultured progenitors suppressed proliferation, decreasing cell number. In vivo, EphA4-/- cortex had a reduced area, fewer cells and less cell division compared with control cortex. To understand the effects of EphA4 signaling in corticogenesis, EphA4-mediated signaling was selectively depressed or elevated in cortical progenitors in vivo. Compared with control cells, cells with reduced EphA4 signaling were rare and mitotically inactive. Conversely, overexpression of EphA4 maintained cells in their progenitor states at the expense of subsequent maturation, enlarging the progenitor pool. These results support a role for EphA4 in the autonomous promotion of cell proliferation during corticogenesis. Although most ephrins were undetectable in cortical progenitors, ephrin B1 was highly expressed. Our analyses demonstrate that EphA4 and ephrin B1 bind to each other, thereby initiating signaling. Furthermore, overexpression of ephrin B1 stimulated cell division of neighboring cells, supporting the hypothesis that ephrin B1-initiated forward signaling of EphA4 promotes cortical cell division.

Key words: Corticogenesis, Neurogenesis, Eph/ephrin, Intercellular communication, Ephrin B1, Mouse


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© The Company of Biologists Ltd 2009