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¹ Division of Neurosciences, Beckman Research Institute of the City of Hope, Duarte, CA 91010
² Program in Developmental Biology, Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109
³ City of Hope Graduate School of Biological Sciences, Duarte, CA 91010
⁴ Department of Cell Biology and Program in Neuroscience, Harvard Medical School, Boston, MA 02115

Correspondence to Qiang Lu: qlu{at}coh.org

Maintaining a balance between self-renewal and differentiation in neural progenitor cells during development is important to ensure that correct numbers of neural cells are generated. We report that the ephrin-B–PDZ-RGS3 signaling pathway functions to regulate this balance in the developing mammalian cerebral cortex. During cortical neurogenesis, expression of ephrin-B1 and PDZ-RGS3 is specifically seen in progenitor cells and is turned off at the onset of neuronal differentiation. Persistent expression of ephrin-B1 and PDZ-RGS3 prevents differentiation of neural progenitor cells. Blocking RGS-mediated ephrin-B1 signaling in progenitor cells through RNA interference or expression of dominant-negative mutants results in differentiation. Genetic knockout of ephrin-B1 causes early cell cycle exit and leads to a concomitant loss of neural progenitor cells. Our results indicate that ephrin-B function is critical for the maintenance of the neural progenitor cell state and that this role of ephrin-B is mediated by PDZ-RGS3, likely via interacting with the noncanonical G protein signaling pathway, which is essential in neural progenitor asymmetrical cell division.

R. Qiu and X. Wang contributed equally to this work.

Alice Davy's present address is Centre de Biologie du Développement, Université de Toulouse/Centre National de la Recherche Scientifique, 31062 Toulouse cedex 9, France.

Abbreviations used in this paper: BrdU, bromodeoxyuridine; CDS, coding sequence; CP, cortical plate; DCX, doublecortin; E, embryonic day; IZ, intermediate zone; p-H3⁺, phospho–Histone H3⁺; RGS, Regulator of G protein Signaling; shRNA, short hairpin RNA; SVZ, subventricular zone; VZ, ventricular zone.

© 2008 Qiu et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jcb.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

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