CXCL12 increases human neural progenitor cell proliferation through Akt-1/FOXO3a signaling pathway.
CXCL12 increases human neural progenitor cell proliferation through Akt-1/FOXO3a signaling pathway.
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DOI：
10.1111/j.1471-4159.2009.06043.x
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发表时间：
2009-05
影响因子：
4.7
通讯作者：
Zheng JC
中科院分区：
文献类型：
--
作者：
Wu Y;Peng H;Cui M;Whitney NP;Huang Y;Zheng JC
趋化因子受体CXCR 4的配体CXCL 12在神经发育过程中介导神经祖细胞（NPC）迁移是众所周知的。然而，CXCL 12对人NPC增殖的影响及其相关的信号通路仍不清楚。转录因子FOXO 3a是Akt-1的下游靶点，对细胞周期控制至关重要，也可能在调节NPC增殖中发挥重要作用。在本研究中，我们发现CXCL 12促进人NPC增殖，如增殖标记物Ki 67和BrdU掺入所确定的。这种CXCL 12介导的NPC增殖与Akt-1和FOXO 3a磷酸化的增加相关，呈时间和剂量依赖性。CXCR 4拮抗剂（T140）或G蛋白抑制剂（PTX）和PI 3 K抑制剂（LY 294002）可阻断CXCL 12介导的NPC增殖以及Akt-1和FOXO 3a的磷酸化。采用腺病毒过表达技术进一步研究Akt-1和FOXO 3a在CXCL 12介导的NPC增殖中的作用。NPC中显性阴性Akt-1或野生型FOXO 3a的过表达消除了CXCL 12介导的增殖。这些数据表明CXCL 12介导的NPC增殖依赖于Akt-1和FOXO 3a的磷酸化，并提供了对CXCL 12在神经发生中的重要作用的见解。了解这一机制可能有助于开发新的治疗靶点，在神经发生过程中的NPC增殖。
CXCL12, a ligand for the chemokine receptor CXCR4, is well known in mediating neural progenitor cell (NPC) migration during neural development. However, the effects of CXCL12 on human NPC proliferation and its associated signaling pathways remain unclear. The transcription factor FOXO3a, a downstream target of Akt-1, is critical for cell cycle control and may also play an important role in regulating NPC proliferation. In this study, we found CXCL12 promotes human NPC proliferation as determined by the proliferation marker Ki67 and BrdU incorporation. This CXCL12-mediated NPC proliferation was associated with an increase in Akt-1 and FOXO3a phosphorylation in a time- and dose-dependent manner. The CXCR4 antagonist (T140) or inhibitors for G proteins (PTX) and PI3K (LY294002) abolished CXCL12-mediated NPC proliferation and phosphorylation of Akt-1 and FOXO3a. The roles of Akt-1 and FOXO3a in CXCL12-mediated NPC proliferation were further investigated by using adenoviral over-expression in NPCs. Over-expression of dominant-negative Akt-1 or wild-type FOXO3a in NPC abrogated CXCL12-mediated proliferation. These data suggest CXCL12-mediated NPC proliferation is reliant upon the phosphorylation of Akt-1 and FOXO3a and gives insight to an essential role of CXCL12 in neurogenesis. Understanding this mechanism may facilitate the development of novel therapeutic targets for NPC proliferation during neurogenesis.
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影响因子：
64.5
作者：
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通讯作者：
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作者：
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DOI：
10.1073/pnas.0406789102
发表时间：
2005-02-01
影响因子：
11.1
作者：
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通讯作者：
Tindall, DJ