细胞周期因子Geminin在斑马鱼体节发生中作用的研究
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摘要
体节发生是胚胎发育研究的一个重要内容,体节是沿身体前后轴形成一定数目的重复性结构,是原体节中胚层(presomite mesoderm)细胞通过边缘间充质细胞角质化(MET)以后形成的细胞团,最终在成体中发育成肌肉和骨骼等相关组织。随着研究的深入,研究者们先后提出了几个体节发生模型,其中最重要的一个是时钟-波峰模型(clock-wave frontmodel),用以解释体节发生的周期性复杂过程。Gem是一重要的细胞周期因子,它与DNA复制关键因子Cdt1发生直接相互作用而抑制Cdt1的功能,从而抑制DNA在同一细胞周期里的二次复制。在我们的工作中,通过干扰Geminin表达后体节形态变化和调控体节发生的信号途径活性的变化,研究Gem在体节发生过程中的功能,并以此为体节发生的经典模型提供实验依据。
我们首先发现,对Geminin翻译阻断(knock down)后,体节前后轴变窄,边缘模糊,正常的“V”形体节发生变形。进一步研究发现,Gem作为一个调控因子在体节发生过程中同时控制了RA-FGF8浓度梯度的形成和调控体节时钟发生的Notch信号途径。当Gem MO后,在体节发生的tailbud和PSM区域,FGF8表达增加,RA合成酶Aldhla2表达减少,从而最终使形成的体节在前后轴方向上变窄。对于控制体节时钟的Notch信号途径,Gem以两种方式参与其调节:一是作为Mib的正调控因子在DNA水平上结合于Mib内含子编码区域,促进Mib的转录;二是以某种不明的方式促进细胞膜表面Notch信号受体DeltaD和DeltaC的转录。因此当其功能缺失以后,Gem以两种方式介导的Notch信号途径的调控均受到阻碍,最后表现为Notch信号活性明显降低,体节发生缺陷。同时我们也发现Gem MO也导致了调节体节极性和细胞粘附的基因表达减弱,使得体节极性和体节发生的MET过程发生缺陷。
其次我们发现细胞周期因子Geminin的功能被阻断后,胚胎发育延迟,体节发生频率减慢。进一步检测H3P活性和细胞凋亡表明这与细胞周期的延长有关,该结论给体节发生的细胞周期模型(cell cycle model)提供一定的实验依据。
以Geminin功能缺失以及其他多种方式改变细胞周期后,使体节发生区域细胞的周期时相发生一定的紊乱,结果发现并没导致振荡基因表达的紊乱。这说明在体节发生中细胞周期协同性不是振荡基因协调表达的关键因素,而Notch信号途径才是振荡基因协调表达的主要调控者。同时我们发现振荡基因的协调表达对Notch信号活性的要求又是非剂量依赖性的,对Notch信号强弱的变化并不敏感。
总之,在胚胎发育中细胞周期因子Geminin作为一多功能分子第一次被发现同时调节体节发生相关的FGF8和Notch信号途径。Geminin功能的缺失上调了FGF8信号途径,同时降低notch信号途径活性,导致体节发生缺陷。Geminin在体节形成过程中的功能也暗示了“clock-front wave”和“cell cycle”两个模型间的内在分子联系。
Somitogenesis is an important developmental event. Somite is a series of repeated structure which appears along the anterior-posterior axis, it is developed from the presomite mesoderm, which undergoes MET at the last step of somitogenesis. After Semites are completely formed, they will further differentiate into muscle, skeleton, and related tissues. With great progresses in the field recently, several research models, including the most important "clock -wave front "model, have been proposed to explain this complicated process. Geminin is a cell cycle regulator directly interacting with the DNA replication initiation factor Cdtl, thus inhibiting DNA rereplication in one cell cycle. In our work, we perturb the function of geminin in zebrafish embryos, and then analyze phenotypes as well as signaling network, hoping to demonstrate the role and mechanism of geminin in somitogenesis. In addition, we hope to provide some experimental evidences to the classic models.
By inhibiting geminin translation via Gem MO injection into the embryo, we first find that the length of somite along the anterior-posterior axis is shorter than that in the wild type, and in the GemMO injected embryos, the somite boundary is not clear, the normal V-shape somite gets malformed. To further study, we find that geminin regulates both RA as well as FGF8 gradients and Notch signaling controling segmentation clock. The transcription of FGF8 and Aldhla2 increases and decreases respectively in GemMO injected embryos, leading to the shorter somite. Furthermore, geminin is involved in the regulation of Notch signaling pathway through two different mechanisms. First, Geminin directly binds to the intron sequence of Mib on the chromatin, working as a positive regulator to enhance Mib transcription. Second, geminin positively regulates the transcription of membrane receptors of Notch, DeltaD and DeltaC. Therefore, when GemMO was injected, the positively regulatory roles of Notch activity by geminin via the above two mechanisms are inhibited, resulting in abnormal somitogenesis. In addition, injection of GemMO was shown to inhibit the transcription of somite polarity gene and adhensive gene, which leads somite polarity defects and disturbed MET.
When the function of geminin was inhibited, the embryonic development is delayed and the rate of somitogenesis decreases. After the activity of phosphorylated histone 3 (H3P) and cell apoptosis in tailbud and PSM region were checked, we find that the delay of somitogenesis is related to the prolonged cell cycle, this result supports the "cell cycle" somitogenesis model.
Knock down of geminin and other cell cycle regulators perturbs the cell cycle, but does not completely destroy segmentation clock and the expression of oscillators. This result indicates that the cell cycle phase is not critical for oscillation itself, which is mainly controled by Notch signaling pathway. In addition, the synchronized expression pattern of oscillatiors is not sensitive to dose of Notch activity.
In conclusion, during development, Geminin works as a multifunctional regulator of FGF8 and Notch signaling. Geminin loss-of-function expands the activity of FGF8, but inhibits the activity of Notch, thus together leading to defective somitogenesis. In addition, the roles of geminin in somitogenesis provide a possible link between the "clock-wave front" model and the "cell cycle" model.
我们首先发现,对Geminin翻译阻断(knock down)后,体节前后轴变窄,边缘模糊,正常的“V”形体节发生变形。进一步研究发现,Gem作为一个调控因子在体节发生过程中同时控制了RA-FGF8浓度梯度的形成和调控体节时钟发生的Notch信号途径。当Gem MO后,在体节发生的tailbud和PSM区域,FGF8表达增加,RA合成酶Aldhla2表达减少,从而最终使形成的体节在前后轴方向上变窄。对于控制体节时钟的Notch信号途径,Gem以两种方式参与其调节:一是作为Mib的正调控因子在DNA水平上结合于Mib内含子编码区域,促进Mib的转录;二是以某种不明的方式促进细胞膜表面Notch信号受体DeltaD和DeltaC的转录。因此当其功能缺失以后,Gem以两种方式介导的Notch信号途径的调控均受到阻碍,最后表现为Notch信号活性明显降低,体节发生缺陷。同时我们也发现Gem MO也导致了调节体节极性和细胞粘附的基因表达减弱,使得体节极性和体节发生的MET过程发生缺陷。
其次我们发现细胞周期因子Geminin的功能被阻断后,胚胎发育延迟,体节发生频率减慢。进一步检测H3P活性和细胞凋亡表明这与细胞周期的延长有关,该结论给体节发生的细胞周期模型(cell cycle model)提供一定的实验依据。
以Geminin功能缺失以及其他多种方式改变细胞周期后,使体节发生区域细胞的周期时相发生一定的紊乱,结果发现并没导致振荡基因表达的紊乱。这说明在体节发生中细胞周期协同性不是振荡基因协调表达的关键因素,而Notch信号途径才是振荡基因协调表达的主要调控者。同时我们发现振荡基因的协调表达对Notch信号活性的要求又是非剂量依赖性的,对Notch信号强弱的变化并不敏感。
总之,在胚胎发育中细胞周期因子Geminin作为一多功能分子第一次被发现同时调节体节发生相关的FGF8和Notch信号途径。Geminin功能的缺失上调了FGF8信号途径,同时降低notch信号途径活性,导致体节发生缺陷。Geminin在体节形成过程中的功能也暗示了“clock-front wave”和“cell cycle”两个模型间的内在分子联系。
Somitogenesis is an important developmental event. Somite is a series of repeated structure which appears along the anterior-posterior axis, it is developed from the presomite mesoderm, which undergoes MET at the last step of somitogenesis. After Semites are completely formed, they will further differentiate into muscle, skeleton, and related tissues. With great progresses in the field recently, several research models, including the most important "clock -wave front "model, have been proposed to explain this complicated process. Geminin is a cell cycle regulator directly interacting with the DNA replication initiation factor Cdtl, thus inhibiting DNA rereplication in one cell cycle. In our work, we perturb the function of geminin in zebrafish embryos, and then analyze phenotypes as well as signaling network, hoping to demonstrate the role and mechanism of geminin in somitogenesis. In addition, we hope to provide some experimental evidences to the classic models.
By inhibiting geminin translation via Gem MO injection into the embryo, we first find that the length of somite along the anterior-posterior axis is shorter than that in the wild type, and in the GemMO injected embryos, the somite boundary is not clear, the normal V-shape somite gets malformed. To further study, we find that geminin regulates both RA as well as FGF8 gradients and Notch signaling controling segmentation clock. The transcription of FGF8 and Aldhla2 increases and decreases respectively in GemMO injected embryos, leading to the shorter somite. Furthermore, geminin is involved in the regulation of Notch signaling pathway through two different mechanisms. First, Geminin directly binds to the intron sequence of Mib on the chromatin, working as a positive regulator to enhance Mib transcription. Second, geminin positively regulates the transcription of membrane receptors of Notch, DeltaD and DeltaC. Therefore, when GemMO was injected, the positively regulatory roles of Notch activity by geminin via the above two mechanisms are inhibited, resulting in abnormal somitogenesis. In addition, injection of GemMO was shown to inhibit the transcription of somite polarity gene and adhensive gene, which leads somite polarity defects and disturbed MET.
When the function of geminin was inhibited, the embryonic development is delayed and the rate of somitogenesis decreases. After the activity of phosphorylated histone 3 (H3P) and cell apoptosis in tailbud and PSM region were checked, we find that the delay of somitogenesis is related to the prolonged cell cycle, this result supports the "cell cycle" somitogenesis model.
Knock down of geminin and other cell cycle regulators perturbs the cell cycle, but does not completely destroy segmentation clock and the expression of oscillators. This result indicates that the cell cycle phase is not critical for oscillation itself, which is mainly controled by Notch signaling pathway. In addition, the synchronized expression pattern of oscillatiors is not sensitive to dose of Notch activity.
In conclusion, during development, Geminin works as a multifunctional regulator of FGF8 and Notch signaling. Geminin loss-of-function expands the activity of FGF8, but inhibits the activity of Notch, thus together leading to defective somitogenesis. In addition, the roles of geminin in somitogenesis provide a possible link between the "clock-wave front" model and the "cell cycle" model.
引文
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