EGF-signaling Mediated by Gab1 Is Required for the Spatiotemporally Regulated Proliferation of Olig2-expressing Progenitors in the Embryonic Spinal Cord

¹ Department of Neurobiology, Graduate School of Medicine, Gifu University, Gifu, Japan; Department of Physiology, Keio University School of Medicine, Tokyo, Japan
² Laboratory for Cytokine Signaling, RIKEN Research Center for Allergy and Immunology, Yokohama, Japan
³ Department of Physiology, Keio University School of Medicine, Tokyo, Japan
⁴ Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo, Japan
⁵ Laboratory for Cytokine Signaling, RIKEN Research Center for Allergy and Immunology, Yokohama, Japan; Laboratory for Developmental Immunology, Graduate School of Frontier Biosciences, Osaka University, Osak, Japan
⁶ Department of Neurobiology, Graduate School of Medicine, Gifu University, Gifu, Japan
⁷ Department of Physiology, Keio University School of Medicine, Tokyo, Japan; Core Research for Evolutional Science Technology (CREST), Solution-Oriented Research for Science and Technology (SORST), Japan Science and Technology Agency (JST), Saitama, Japan

^* To whom correspondence should be addressed. E-mail: shimazak{at}sc.itc.keio.ac.jp.

	Abstract

Gab1 (Grb2 associated binder1) has been identified as an adaptor molecule downstream of many growth factors, including EGF, FGFs and PDGF which have been shown to play crucial roles as mitotic signals for a variety of neural progenitor cells, including stem cells, both in vitro and in vivo. Here, we show that Gab1 deficiency results in a reduction in the number of Olig2-positive (Olig2⁺) progenitor cells in the developing mouse spinal cord after E12.5, when gliogenesis starts in the pMN domain where the EGF receptor (EGFR) is expressed predominantly. Our in vitro analysis further revealed that Gab1 is essential for EGF-dependent proliferation of Olig2⁺ progenitor cells derived from the E12.5 ventral and E14.5 dorsal but not ventral spinal cord, while Gab1 is always required for the activation of Akt1, but not of ERK1/2. Moreover, we found that the action of Gab1/Akt pathway is context-dependent, since constitutively active Akt1 could rescue the proliferation defect only in the E12.5 spinal cord of Gab1-deficient mouse in vitro. Finally, we demonstrated that EGFR-deficient mice and Gab1-deficient mice showed a similar reduction in the number of Olig2⁺ progenitor cells in the developing spinal cord. These findings indicate that EGFR mediated signaling through Gab1/Akt contributes to the sufficient expansion of Olig2⁺ progenitor cells in a spatiotemporally regulated manner, which represent the origin of glial cells in the developing spinal cord.

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