VEGF activates divergent intracellular signaling components to regulate retinal progenitor cell proliferation and neuronal differentiation
VEGF activates divergent intracellular signaling components to regulate retinal progenitor cell proliferation and neuronal differentiation
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DOI：
10.1242/dev.02385
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发表时间：
2006-06-01
期刊：
影响因子：
4.6
通讯作者：
Yang, Xian-Jie
中科院分区：
文献类型：
--
作者：
Hashimoto, Takao;Zhang, Xiang-Mei;Yang, Xian-Jie
在脊椎动物神经发生过程中，多种细胞外信号影响祖细胞的命运选择。未定型祖细胞解释和整合信号的过程还不清楚。我们在这里证明，在无血管的鸡视网膜，有丝分裂后神经元分泌的血管内皮生长因子（VEGF）的行为通过FLK 1受体存在于祖细胞影响细胞增殖和承诺。增强VEGF信号增加祖细胞增殖并减少视网膜神经节细胞发生。相反，吸收内源性VEGF配体或破坏FLK 1活性会减弱细胞增殖并增强视网膜神经节细胞的产生。此外，我们提供的证据表明，由FLK 1受体传递的VEGF信号激活不同的细胞内信号传导成分，调节祖细胞的不同反应。VEGF诱导的增殖受MEK-ERK途径以及碱性螺旋-环-螺旋因子HES 1的影响。相比之下，VEGF依赖性神经节细胞抑制不需要MEK-ERK激活，而是依赖于VEGF刺激的HES 1活性，这与NOTCH信号无关。此外，升高的HES 1表达促进祖细胞增殖，并防止由于VEGF或音刺猬（SHH）（抑制神经节细胞发育的另一种信号）的丢失而导致的视网膜神经节细胞的过度产生。基于以前和目前的研究结果，我们提出，HES 1作为一个收敛的信号节点内的早期视网膜祖细胞整合各种细胞的外在线索，包括VEGF和SHH，以控制细胞增殖和神经元的规格。
During vertebrate neurogenesis, multiple extracellular signals influence progenitor cell fate choices. The process by which uncommitted progenitor cells interpret and integrate signals is not well understood. We demonstrate here that in the avascular chicken retina, vascular endothelial growth factor ( VEGF) secreted by postmitotic neurons acts through the FLK1 receptor present on progenitor cells to influence cell proliferation and commitment. Augmenting VEGF signals increases progenitor cell proliferation and decreases retinal ganglion cell genesis. Conversely, absorbing endogenous VEGF ligand or disrupting FLK1 activity attenuates cell proliferation and enhances retinal ganglion cell production. In addition, we provide evidence that VEGF signals transmitted by the FLK1 receptor activate divergent intracellular signaling components, which regulate different responses of progenitor cells. VEGF-induced proliferation is influenced by the MEK-ERK pathway, as well as by the basic helix-loop-helix factor HES1. By contrast, VEGF-dependent ganglion cell suppression does not require MEK-ERK activation, but instead relies on VEGF-stimulated HES1 activity, which is independent of NOTCH signaling. Moreover, elevated HES1 expression promotes progenitor cell proliferation and prevents overproduction of retinal ganglion cells owing to the loss of VEGF or sonic hedgehog ( SHH), another signal that suppresses ganglion cell development. Based on previous and current findings, we propose that HES1 serves as a convergent signaling node within early retinal progenitor cells to integrate various cell-extrinsic cues, including VEGF and SHH, in order to control cell proliferation and neuronal specification.