Epidermal growth factor signaling mediated by grb2 associated binder1 is required for the spatiotemporally regulated proliferation of olig2-expressing progenitors in the embryonic spinal cord.
Gab1 (Grb2 associated binder1) has been identified as an adaptor molecule downstream of many growth factors, including epidermal growth factor (EGF), fibroblast growth factor, and platelet-derived growth factor, 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 embryonic day 12.5 (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, whereas Gab1 is always required for the activation of Akt1 but not of ERK1/2. Moreover, we found that the action of the Gab1/Akt pathway is context-dependent, since constitutively active Akt1 could rescue the proliferation defect only in the E12.5 spinal cord of the 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 represents the origin of glial cells in the developing spinal cord. Disclosure of potential conflicts of interest is found at the end of this article.
Hayakawa-Yano
Yoshika
Y
Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
Nishida
Keigo
K
Fukami
Shinichi
S
Gotoh
Yukiko
Y
Hirano
Toshio
T
Nakagawa
Toshiyuki
T
Shimazaki
Takuya
T
Okano
Hideyuki
H
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D002452:Cell Count; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D004815:Epidermal Growth Factor / Q000378:metabolism* / Q000502:physiology; D018507:Gene Expression Regulation, Developmental; D018773:Genes, erbB-1 / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000166:cytology; D000076104:Oligodendrocyte Transcription Factor 2; D051058:Oncogene Protein v-akt / Q000502:physiology; D010750:Phosphoproteins / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013116:Spinal Cord / Q000187:drug effects / Q000196:embryology* / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D051792:Basic Helix-Loop-Helix Proteins; D004815:Epidermal Growth Factor; D009419:Nerve Tissue Proteins; D000076104:Oligodendrocyte Transcription Factor 2; D051058:Oncogene Protein v-akt; D010750:Phosphoproteins; C490897:Gab1 protein, mouse; C512773:Olig2 protein, mouse