摘要
(一)δ-SG是肌聚糖复合物的成员,它在各种脊椎动物的骨骼肌和心肌中特异表达。肌聚糖复合物基因的突变在人类中与肢带型肌营养不良症(LGMD)和扩张型心肌病(DCM)相关。在本文中,我们克隆了斑马鱼δ-SG基因,并研究了其在胚胎发育时期的表达谱,并通过吗啉修饰的反义寡核苷酸介导的基因抑制深入研究了该基因在斑马鱼胚胎发育过程中的功能。
斑马鱼δ-SG基因全长cDNA的长度为1938bp,其中的开放阅读框编码了一条含有290个氨基酸残基的多肽。该基因表达产物在氨基酸水平上与人、小鼠、仓鼠、鸡的δ-SG基因产物分别有72%、73%、73%和69%的相似性。δ-SG的基因组序列分析显示该基因由8个外显子和7个内含子组成,覆盖了长将近200kb的基因组区域。原位杂交结果显示δ-SG的表达最初开始于分节期早期。高水平的δ-SG表达出现在骨骼肌和心肌。其它如眼部和下颚肌肉、胸鳍、鳃弓、和鳔也有显著的表达。此外受精三天后,在中脑和视网膜也能观测到δ-SG表达。
我们采用吗啉修饰的反义RNA进行基因抑制,结果显示绝大多数注射δ-SG-MO的斑马鱼胚胎都显示出严重的异常表型;发育不全的头部,线性心脏,微弱的心跳和短小的躯干,并且大多在5天内死亡。而注射同样剂量的对照MO的胚胎发育与正常胚胎没有明显区别。MO-GFP和拯救实验证据也有效的证实使用的MO能抑制内源δ-SG蛋白的翻译。原位杂交分析显示在受累胚胎中,近轴细胞和肌肉前体细胞减少。δ-SG基因表达的缺失严重阻碍了心脏早期发育过程,并影响了心肌细胞的分化。更有趣的是心脏的左右非对称模式发生了改变。同时免疫印记分析显示SG复合物相关蛋白的表达量在MO注射胚胎中明显下调,甚至基本消失。这些结果显示δ-SG在早期心脏和肌肉的发育中具有很重要的作用,我们推测SG复合物可能作为膜受体参与早期发育的信号传递。
(二)
Forkhead转录因子家族一类由许多调控分子组成的大家族,它们共同拥有一个保守的110个氨基酸残基的DNA结合域——forkhead结构域。该家族在包括脑、心血管系统、肺、肠和肾等组织的发育过程中都发挥重要作用。其功能包括参与细胞增殖,分化,染色体重塑,有丝分裂过程和转化过程等。本文中我们克隆了斑马鱼Foxp1基因(Genebank序列号为DQ333303),进行了生物信息学分析,并研究了其表达谱。
斑马鱼Foxp1全长cDNA的长度为2440bp,其中的开放阅读框编码了一条含有659个氨基酸残基的多肽。该基因表达产物在氨基酸水平上与人、小鼠、仓鼠、鸡、云雀和爪蟾的Foxp1基因产物分别有72%、68%、68%、70%、65%和62%的相似性。其中包含一个锌指结构域,一个亮氨酸拉链和一个Forkhead DNA结合域。通过5'RACE和RT-PCR分析发现了4个Foxp1可变剪接体A型—D型。整胚原位杂交和RT—PCR结果显示在胚胎发育阶段Foxp1的时空表达谱是非常复杂而动态的,尤其是在神经系统的发育过程中。各可变剪接体的时空表达谱有很大区别,其中高量的母源表达主要为D型,B型也主要在胚胎发育中期表达,A型和C型可能为幼鱼及成体后的主要表达类型。该基因在中枢神经系统的许多区域都有表达,特别是中后脑分界线,后脑和脊索。同时Foxp1在视网膜、耳、鳃弓、孵化腺、心脏、原肾管、肠道、原肛、胸鳍和鳔等部位都有广泛的高表达。
通过对斑马鱼基因功能的研究可以揭示其在斑马鱼发育过程中所起的作用。在本文中我们采用morpholino进行Foxp1基因抑制,结果显示大多数注射Foxp1-MO的斑马鱼胚胎出现一致的表型,主要集中在脑部发育和心脏发育障碍,此外还有躯干弯曲,孵化腺细胞异常等。而注射同样剂量的对照MO的胚胎发育与正常胚胎没有明显区别。这些结果表明斑马鱼Foxp1基因在启动胚胎发育和其后的组织器官发生如神经系统、心脏和其它多个组织中都有重要的作用。
(1)
δ-SG,one member of the sarcoglycan complex,is a very conservative muscle specific protein exclusively expressed in the skeletal and cardiac muscle of vertebrates.Mutations in sarcoglycans are known to be involved in limb-girdle muscular dystrophy(LGMD)and dilated cardiomyopathy(DCM)in humans.Here we report molecular cloning,characterization and developing expression of a novel zebrafishδ-SG gene.And we adopte the gene-specific morpholino modified antisense oligo to carry out gene knock-down assay and analysis its influence to zebrafish embryogenesis.
The full length of zebrafishδ-SG cDNA is 1938 bp and it encodes a polypeptide of 290 amino acids which shares 72%,73%,73% and 69% overall identity with human,mouse,hamster and chickenδ-SG,respectively.Characterization of zebrafishδ-SG genomic sequence reveals that it spans about 200kb and contains eight exons and seven introns.The expression pattern ofδ-SG in zebrafish embryonic development is studied by whole-mount in situ hybridization.The onset of zygotic transcription is at early segmentation period.Strong expression ofδ-SG was observed in various muscles including those of the segment,heart,eye,jaw,pectoral fin, branchial arches and swim bladder in zebrafish embryo.Expression could also be found in midbrain and retina after 72hpf.
Furthermore,we carry out gene knock-down by morpholino modified antisense oligonucleotide.The MO-injected embryos showed severe abnormality in both the cardiac and skeletal muscle.However,the embryos injected with the same dose control mopholino oligonucleotide showed no difference from the uninjected wildtype embryos.Tthe evidences provided by MO-GFP and rescue experiment are valid enough to confirm that MO effectively represses the translation ofδ-SG protein.Some severe ones had serious morphological abnormality such as hypoplastic head,linear heart,very weak heartbeats and runtish trunk,all dead within 5 dpf.Whole-mount in situ hybridization analysis showed that inδ-SG knockdown embryos adaxial cells and muscle pioneers were affected.In addition,absence ofδ-SG protein severely delayed the cardiac development and influenced the differentiation of cardiac muscle,and the cardiac left-right asymmetry was dramatically changed in morpholino treated embryos.Immunoblot analysis shows downregulation of the sarcoglycans.These data together suggest thatδ-SG plays an important role in early heart and muscle development.
(2)
The winged-helix/forkhead transcription factor gene family is a large group of proteins that share a conserved 110-amino acid DNA-binding domain termed as winged-helix or forkhead domain.Members of this family have been shown to play important roles in the development of various organs,including brain,cardiovascular system,lung,gut and kidney,with their diverse functions including pro-liferation, cellular differentiation,chromatin remodeling,mitotic program,and neoplastic transformation.In this report,we described the isolation,characterization and expression of Foxp1 in zebrafish.
The full-length zebrafish Foxp1 cDNA was 2440bp encoding a 659-amino-acid protein which shares 72%,68%,68%,70%,65%,and 62% overall identity with human,mouse,rat,chicken,avian,and frog Foxp1,respectively.The product of Foxp1 gene contains a zinc-finger domain,a leueine zipper domain and a forkhead domain.5'RACE and RT-PCR have confirmed that zebrafish Foxp1 transcripts contain at least four different splicing variants named Foxp1A-D.The results of whole-mount in situ hybridization and RT-PCR showed Foxp1 have very complex and dynamic expression pattern during early embryonic development.The spatial and temporal expression patterns of four splice isoforms are different.Remarkable signals of Foxpl were detected in many domains of the developing central nervous system, especially in mid-hind brain boundary,hindbrain,and spinal cord.Strong and broad expression was also observed in retina,ear,branchial arches,hatching gland,heart, pronephric duct,gut,proctodeum,pectoral fin and swim bladder.
Knock-down had been used in studying the gene function in zebrafish development.Almost all the Foxp1-MO-injected show highly consistant phynotype including hypoplastic head,small eyes,pericardial edema and weak heartbeats.The embryos injected with the same dose control mopholino oligonucleotide showed no difference from the uninjeeted wildtype embryos.These results provide evidence that Foxp1 might be very important in the development of the central nervous system, heart and many other organs.
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