Science重大突破:震撼视频!哈佛科学家揭示“胚胎发育”最详细过程
2018/05/02
一个受精卵究竟是如何产生构成完整身体的多种细胞类型、组织和器官的?这是生物学领域最大的谜题之一。如今,结合单细胞测序技术和新型计算工具,来自哈佛大学、Broad研究所等机构的科学家们提供了关于这一过程最详细的图片。4月26日,Science杂志用3篇论文报道了这一突破性成果。

How one cell gives rise to an entire body(视频地址:https://v.qq.com/x/page/o0638d3wb5n.html)小编温馨提示:视频内容非常震撼,但是也有点……(有密集恐惧症的小伙伴做好心理准备哦)。

为了追踪数千个细胞及其后代的新身份,研究者们首先在特殊的溶液中温和地溶解不同阶段的胚胎,接着摇晃或搅拌胚胎溶解物以释放单个细胞,之后测定每个细胞所有信使RNA(mRNA,反应了基因被转录的情况)链的序列。在获得了“正在发育的斑马鱼或青蛙胚胎中大部分细胞中基因活性的多个快照”后,他们最终拼凑出了胚胎形成的连贯历史coherent histories,详见以上视频)。

三篇论文


图片来源:Science(DOI: 10.1126/science.aar5780)


图片来源:Science(DOI: 10.1126/science.aar4362)

3篇论文中,题为“The dynamics of gene expression in vertebrate embryogenesis at single-cell resolution”和“Single-cell mapping of gene expression landscapes and lineage in the zebrafish embryo”的论文是由哈佛医学院的Allon Klein、Marc Kirschner和Sean Megason领导的团队完成的。他们专注于研究斑马鱼和青蛙,这也是发育生物学家研究了几十年的两种脊椎动物。

在斑马鱼研究中,Klein 和Megason分析了约92,000个斑马鱼细胞,收集了来自7个不同胚胎阶段的mRNA数据。研究小组从发育了4小时的胚胎开始调查,在受精后24小时(这是基本器官开始出现的时间点)结束。每个细胞的基因活动模式表明了它的发展方向,并最终揭示了它的身份。


In a close-up of a zebrafish embryo, green and red fluorescence marks cells specializing into different tissues.(Blue highlights cellular DNA.) 图片来源:Science

为了追踪细胞及其后代是如何随时间变化的,研究人员给一些单细胞鱼胚胎(single-cell fish embryo)植入了基因示踪剂(genetic tracers):许多微小的独特DNA片段被注入到胚胎的细胞质中。当细胞在不断成长的胚胎中反复分裂时,这些“条形码”(barcodes,也就是基因示踪剂)会进入细胞核,并被“合并”到染色体中。实验结束时,每个细胞谱系最终都会形成一个独特的条形码组合。通过将这些信息与基因活动特征(gene activity profiles)结合起来,研究小组能够通过时间来追踪细胞的命运,看看一个受精卵是如何产生各种特殊细胞的,如心脏细胞、神经细胞和皮肤细胞。


图片来源:Science(DOI: 10.1126/science.aar3131)

在题为“Single-cell reconstruction of developmental trajectories during zebrafish embryogenesis”的第3篇论文中,哈佛大学的发育生物学家Alexander Schier开发了自己的计算方法,以追踪成熟斑马鱼中的细胞。

在研究小组对胚胎早期生长阶段的细胞进行取样(在胚胎发育最初的9个小时中,每45分钟取一次样),以及对这些细胞的mRNA进行测序后,软件能够通过提取完全分化的细胞的基因活性并分析在次老胚胎(the next-oldest embryo)中哪些细胞具有最相似的基因活动特征谱来重建每个细胞的发育史。最终,Schier等证实,最初的单细胞胚胎(initial one-celled embryo)能够产生25种主要的细胞类型。

意外发现

作者们指出,这些分析也产生了一些意外。发育生物学家曾经认为,一旦一个细胞开始沿着一个方向发展(如发育成一个肌肉细胞),那它就不会“偏离”这个方向。然而,这项新研究发现,一些斑马鱼细胞会在“半路”转向另一个发展方向(即,发育成不同的细胞类型)。“‘这幅画’比我们想象的要复杂得多。”Megason感慨道。

物种差异

在青蛙(Xenopus tropicalis)研究中,Kirschner和Klein对受精后5到22小时内的10个胚胎阶段进行了单细胞RNA测序分析。他们的团队最终读取了137,000个细胞的mRNA。基因活动数据显示,即使青蛙胚胎看起来还只是一个未分化的团(blob),它的细胞也已经开始接受它们的最终身份了。

在比较青蛙和斑马鱼的结果时,Klein等发现了惊人的差异,例如,某些细胞类型的发育路线会因物种而异。此外,虽然关键转录因子基因的活性在两个物种的普通细胞类型中是相似的,但这两个物种之间,某些细胞类型中的其他基因的活性差异比研究人员预期的要大得多。

同行评价

柏林医学系统生物学研究所的发育生物学家Robert Zinzen说:“看到这些成果,我的第一反应是:Wow!尽管不久前Science刚刚报道了研究人员在被切碎后再生的涡虫(简单的扁形虫,无脊椎)中追踪cell-by-cell基因活性的成果,但在脊椎动物中,复杂性要高得多。

美国华盛顿大学的发育生物学家David Kimelman则表示,这些新成果是一项重要成就,能够帮助理解发育生物学中关键的基础问题。

责编:风铃

参考资料:

How one cell gives rise to an entire body

Chronicling embryos, cell by cell, gene by gene

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