gna13，lrp8基因在斑马鱼胚胎发育中的功能研究
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摘要
异源三聚体鸟苷酸结合蛋白(G蛋白)作为一种重要的信号转导因子参与调控多种生理过程。G蛋白分为四大家族：Gs,Gi,Gq和G12。G13属于G12家族,其基因名称为gna13。有研究表明Gα13敲除小鼠胚胎的脉管系统出现严重缺陷并在孕后约9.5天死亡。然而,该现象背后的分子机理尚未阐明。斑马鱼具有两种不同的Gα13转录本：Gα13a和Gα13b。在斑马鱼发育早期,Gα12/13促进翻转和延伸运动以促进原肠胚的正常形成。其调节外包的分子机理可能一方面通过限制E-cadherin的活性来实现,另一方面通过调节肌动蛋白细胞骨架的组织来实现。在本研究中,我们发现,沉默Gα13的表达会导致斑马鱼造血系统和血管系统缺陷。Gα13b的下调使得血液循环完全消失。Gatal, pu.1, flk等血细胞或血管标记基因亦下调表达。进一步研究发现在Gα13b缺失的胚胎中,血细胞和血管内皮细胞历经P53介导的细胞凋亡。降低P53的表达可使细胞免于死亡从而部分拯救了Gα13b缺失胚胎的表型。血细胞和血管标记基因的表达亦得到恢复。这些结果提示了Gα13在细胞存活中的新功能。
LRP8是低密度脂蛋白受体超家族成员之一。斑马鱼的lrp8序列通过其基因组序列预测拼接得到,而从未得到实验验证。本研究首次用实验的方法克隆验证了该序列,并发现其比网上预测序列多出一条长57bp的片段。在胚胎发育的体节期,lrp8在头部腹面菱脑原节的四处特定细胞中特异表达。同时在卵黄囊表面也可以检测到均匀的呈点状分布的阳性信号。在胚胎发育至2天后,lrp8主要在中枢神经系统中,特别是在头部中线处以及侧线表达。进一步研究发现,lrp8的缺失会抑制脊髓神经轴突的生长以及髓鞘的形成。这为我们进一步研究lrp8作用的分子机理奠定了基础。
Heterotrimeric guanine nucleotide-binding proteins (G proteins) function as signal transducers and control many different physiologic processes. G proteins can be grouped into four families Gs, Gi, Gq and G12. Gα13,with its gene name gan13,belongs to the G12 family. The Ga13(?)mouse embryos have defective vascular systems and display embryonic lethality (-E9.5), but the molecular basis that underlies the vascular defect observed in Gα13(?) mouse embryos has not been defined. In zebrafish, there are two isoforms of Gα13:Gα13a and Gα13b. During zebrafish gastrulation, Ga12/13 are required for convergence and extension (CE) movements. Ga12/13 might regulate epiboly through two distinct mechanisms by limiting E-cadherin activity and modulating the organization of the actin cytoskeleton. We show here that knockdown of Gα13 in zebrafish results in hematopoietic and angiogenic defects. The Gα13b morphants show complete loss of blood circulation. The expression of hematopoietic and angiogenic markers such as gata1,pu.l,flk were also lost. Further studies reveal that blood cells and vascular endothelial cells have undergone apoptosis through a p>53-dependent pathway in Gα13b-depleted embryos. Injection of p53 morpholino could partially rescue the phenotype of Ga13b morphants and restore the expression of hematopietic and angiogenic markers. These data demonstrate a new role for Gα13 in cell survival.
Lrp8 belongs to the low-density lipoprotein receptor super family. The sequence of Irp8 homology in zebrafish was predicted based on the genomic sequences and has not verified by experiments. In this study, we firstly cloned its cDNA and found our sequence with an additional 57bp fragment to the predicted one. During the late segmentation, lrp8 specifically expresses in four groups of cells in the rhombomere. Its signals can also be detected throughout the surface of yolk sac as presented in pairs of spots. In the embryos of 2dpf or older, Irp8 expresses highly in the centre nerve system, especially in the middle line of the brain. Further study revealed that the lost of Irp8 would suppress the myelination as well as axon growth. All these results will contribute to further study of the molecular mechanism under this process.
LRP8是低密度脂蛋白受体超家族成员之一。斑马鱼的lrp8序列通过其基因组序列预测拼接得到,而从未得到实验验证。本研究首次用实验的方法克隆验证了该序列,并发现其比网上预测序列多出一条长57bp的片段。在胚胎发育的体节期,lrp8在头部腹面菱脑原节的四处特定细胞中特异表达。同时在卵黄囊表面也可以检测到均匀的呈点状分布的阳性信号。在胚胎发育至2天后,lrp8主要在中枢神经系统中,特别是在头部中线处以及侧线表达。进一步研究发现,lrp8的缺失会抑制脊髓神经轴突的生长以及髓鞘的形成。这为我们进一步研究lrp8作用的分子机理奠定了基础。
Heterotrimeric guanine nucleotide-binding proteins (G proteins) function as signal transducers and control many different physiologic processes. G proteins can be grouped into four families Gs, Gi, Gq and G12. Gα13,with its gene name gan13,belongs to the G12 family. The Ga13(?)mouse embryos have defective vascular systems and display embryonic lethality (-E9.5), but the molecular basis that underlies the vascular defect observed in Gα13(?) mouse embryos has not been defined. In zebrafish, there are two isoforms of Gα13:Gα13a and Gα13b. During zebrafish gastrulation, Ga12/13 are required for convergence and extension (CE) movements. Ga12/13 might regulate epiboly through two distinct mechanisms by limiting E-cadherin activity and modulating the organization of the actin cytoskeleton. We show here that knockdown of Gα13 in zebrafish results in hematopoietic and angiogenic defects. The Gα13b morphants show complete loss of blood circulation. The expression of hematopoietic and angiogenic markers such as gata1,pu.l,flk were also lost. Further studies reveal that blood cells and vascular endothelial cells have undergone apoptosis through a p>53-dependent pathway in Gα13b-depleted embryos. Injection of p53 morpholino could partially rescue the phenotype of Ga13b morphants and restore the expression of hematopietic and angiogenic markers. These data demonstrate a new role for Gα13 in cell survival.
Lrp8 belongs to the low-density lipoprotein receptor super family. The sequence of Irp8 homology in zebrafish was predicted based on the genomic sequences and has not verified by experiments. In this study, we firstly cloned its cDNA and found our sequence with an additional 57bp fragment to the predicted one. During the late segmentation, lrp8 specifically expresses in four groups of cells in the rhombomere. Its signals can also be detected throughout the surface of yolk sac as presented in pairs of spots. In the embryos of 2dpf or older, Irp8 expresses highly in the centre nerve system, especially in the middle line of the brain. Further study revealed that the lost of Irp8 would suppress the myelination as well as axon growth. All these results will contribute to further study of the molecular mechanism under this process.
引文
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