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
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
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DOI：
10.1634/stemcells.2006-0584
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发表时间：
2007-06-01
期刊：
影响因子：
5.2
通讯作者：
Okano, Hideyuki
中科院分区：
文献类型：
--
作者：
Hayakawa-Yano, Yoshika;Nishida, Keigo;Okano, Hideyuki
GAB1(Grb2 Associated Binder1)是多种生长因子下游的接头分子，包括表皮生长因子(EGF)、成纤维细胞生长因子和血小板衍生生长因子，这些生长因子在体内外对包括干细胞在内的多种神经前体细胞具有重要的有丝分裂信号作用。在这里，我们表明，GAB1缺乏导致胚胎12.5天(E12.5)后发育中的小鼠脊髓中Orig2阳性(Otl2(+))祖细胞的数量减少，此时胶质形成开始在EGF受体(EGFR)主要表达的PMN区域开始。我们的体外分析进一步表明，GAB1对于E12.5腹侧和E14.5背侧而不是腹侧脊髓来源的寡聚2(+)祖细胞的EGF依赖的增殖是必不可少的，而GAB1总是激活Akt1而不是ERK1/2所必需的。此外，我们发现GAB1/Akt通路的作用是上下文依赖的，因为结构性激活的Akt1只能在体外修复GAB1缺陷小鼠E12.5脊髓的增殖缺陷。最后，我们证明了EGFR缺陷的小鼠和GAB1缺陷的小鼠在发育中的脊髓中显示出相似的Olob2(+)祖细胞数量的减少。这些发现表明，EGFR通过GAB1/Akt介导的信号通路有助于以时空调节的方式充分扩增寡聚2(+)祖细胞，这代表了发育中的脊髓中神经胶质细胞的起源。
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.