DISC1-dependent switch from progenitor proliferation to migration in the developing cortex.
DISC1-dependent switch from progenitor proliferation to migration in the developing cortex.
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DOI：
10.1038/nature09859
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发表时间：
2011-05-05
期刊：
影响因子：
64.8
通讯作者：
Sawa, Akira
中科院分区：
文献类型：
--
作者：
Ishizuka, Koko;Kamiya, Atsushi;Oh, Edwin C.;Kanki, Hiroaki;Seshadri, Saurav;Robinson, Jon F.;Murdoch, Hannah;Dunlop, Allan J.;Kubo, Ken-ichiro;Furukori, Keiko;Huang, Beverly;Zeledon, Mariela;Hayashi-Takagi, Akiko;Okano, Hideyuki;Nakajima, Kazunori;Houslay, Miles D.;Katsanis, Nicholas;Sawa, Akira
皮质醇形成过程中，从祖细胞增殖到神经元迁移的调控机制还知之甚少。在这里，我们报道了DISC1的磷酸化，它是几种精神障碍的主要易感因素，起着从维持有丝分裂前体细胞的增殖到激活有丝分裂后神经元迁移的分子开关的作用。非磷酸化的DISC1通过与Gsk3β的相互作用来调节典型的Wnt信号，而丝氨酸710(S710)的特异性磷酸化则触发Bardet-Biedl综合征(BBS)蛋白向中心体的募集。为了支持这一模型，BBS1的丢失会导致迁移缺陷，但不会导致增殖，而DISC1基因敲除会导致两者的缺陷。磷酸死亡的突变体只能挽救增殖，而模拟磷酸的突变只能挽救迁移缺陷。这些数据强调了DISC1在皮质发生中的双重作用，并表明该蛋白在S710处的磷酸化激活了一个关键的发育开关。
Regulatory mechanisms governing the sequence from progenitor cell proliferation to neuronal migration during corticogenesis are poorly understood. Here we report that phosphorylation of DISC1, a major susceptibility factor for several mental disorders, acts as a molecular switch from maintaining proliferation of mitotic progenitor cells to activating migration of postmitotic neurons. Unphosphorylated DISC1 regulates canonical Wnt signaling via an interaction with GSK3β, whereas specific phosphorylation at Serine 710 (S710) triggers the recruitment of Bardet-Biedl-Syndrome (BBS) proteins to the centrosome. In support of this model, loss of BBS1 leads to defects in migration, but not proliferation, while DISC1 knockdown leads to deficits in both. A phospho-dead mutant can only rescue proliferation, while a phospho-mimic mutant rescues exclusively migration defects. These data highlight a dual role for DISC1 in corticogenesis and suggest that phosphorylation of this protein at S710 activates a key developmental switch.
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影响因子：
30.8
作者：
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通讯作者：
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影响因子：
21.3
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Sawa, Akira
影响因子：
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