Vg1-Nodal heterodimers are the endogenous inducers of mesendoderm.
Vg1-Nodal heterodimers are the endogenous inducers of mesendoderm.
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DOI：
10.7554/elife.28183
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发表时间：
2017-11-15
期刊：
影响因子：
7.7
通讯作者：
Schier AF
中科院分区：
文献类型：
--
作者：
Montague TG;Schier AF
结节被认为是脊椎动物胚胎和胚胎干细胞中内胚层的关键诱导物。其他与转化生长因子β相关的信号，如Vg1/Dvr1/GDF3，也参与了这一过程，但它们的作用尚不清楚或存在争议。在这里，我们报道了没有母体提供的vg1的斑马鱼胚胎不能形成内胚层和头部和躯干中胚层，并且与节点功能丧失突变体非常相似。虽然Nodal的加工和分泌没有Vg1，但它的内源活性需要Vg1。相反，Vg1是未经处理的，存在于内质网中，没有Nodal，只有在Nodal存在的情况下才能分泌、处理和激活。Nodal和Vg1的共表达导致异源二聚体的形成和中胚层的诱导。因此，中胚层的诱导依赖于两个与转化生长因子-β相关的信号的结合：母体和普遍存在的Vg1，以及合子和定位的Nodal。模型显示，母体Vg1池在低浓度的合子节点时能够快速发出信号。所有的动物都是从一个细胞--受精卵开始的。为了成为一个可辨认的成年人，每个胚胎需要产生三种最终形成所有器官的组织：内胚层，它将形成内脏；中胚层，它将形成肌肉和骨骼；外胚层，它将产生皮肤和神经系统。所有脊椎动物--像鱼和人一样有脊椎的动物--使用所谓的节点信号通路来制造内胚层和中胚层。Node是一种信号分子，它与细胞表面的受体结合。如果Nodal与细胞上的受体结合，它就会指示该细胞成为内胚层或中胚层。因此，节节对脊椎动物的生命至关重要。然而，在发育生物学领域，一种名为Vg1的蛋白质是否在脊椎动物的早期发育中发挥了作用，这一问题已经争论了30年。Vg1的分子结构与Nodal相似。斑马鱼经常被用来研究动物的发育，蒙塔古和希耶决定测试这些鱼是否需要Vg1(也称为GDF3)基因，方法是使用一种名为CRISPR/Cas9的基因组编辑技术将其删除。事实证明，雌性斑马鱼可以在没有这种基因的情况下存活。然而，当这些雌性的后代没有从母亲那里继承制造Vg1的指令时，它们就无法形成内胚层和中胚层。这意味着胚胎没有心脏、血液或其他内脏，它们会在三天内死亡。另外两组研究人员也独立报告了类似的结果。研究结果表明，Vg1对斑马鱼Nodal信号通路的工作至关重要。蒙塔古和希耶随后证明，在这一途径中，Nodal不会自行激活其受体。相反，Nodal必须与Vg1相互作用，正是这种Nodal-Vg1复合体激活了受体，并指示细胞成为内胚层和中胚层。科学家目前使用Nodal信号通路来诱导实验室中生长的人类胚胎干细胞成为中胚层和内胚层。因此，这些新发现最终可能有助于研究人员为人类患者培养组织和器官。
Nodal is considered the key inducer of mesendoderm in vertebrate embryos and embryonic stem cells. Other TGF-beta-related signals, such as Vg1/Dvr1/Gdf3, have also been implicated in this process but their roles have been unclear or controversial. Here we report that zebrafish embryos without maternally provided vg1 fail to form endoderm and head and trunk mesoderm, and closely resemble nodal loss-of-function mutants. Although Nodal is processed and secreted without Vg1, it requires Vg1 for its endogenous activity. Conversely, Vg1 is unprocessed and resides in the endoplasmic reticulum without Nodal, and is only secreted, processed and active in the presence of Nodal. Co-expression of Nodal and Vg1 results in heterodimer formation and mesendoderm induction. Thus, mesendoderm induction relies on the combination of two TGF-beta-related signals: maternal and ubiquitous Vg1, and zygotic and localized Nodal. Modeling reveals that the pool of maternal Vg1 enables rapid signaling at low concentrations of zygotic Nodal. All animals begin life as just one cell – a fertilized egg. In order to make a recognizable adult, each embryo needs to make the three types of tissue that will eventually form all of the organs: endoderm, which will form the internal organs; mesoderm, which will form the muscle and bones; and ectoderm, which will generate the skin and nervous system. All vertebrates – animals with backbones like fish and humans – use the so-called Nodal signaling pathway to make the endoderm and mesoderm. Nodal is a signaling molecule that binds to receptors on the surface of cells. If Nodal binds to a receptor on a cell, it instructs that cell to become endoderm or mesoderm. As such, Nodal is critical for vertebrate life. However, there has been a 30-year debate in the field of developmental biology about whether a protein called Vg1, which has a similar molecular structure as Nodal, plays a role in the early development of vertebrates. Zebrafish are often used to study animal development, and Montague and Schier decided to test whether these fish need the gene for Vg1 (also known as Gdf3) by deleting it using a genome editing technique called CRISPR/Cas9. It turns out that female zebrafish can survive without this gene. Yet, when the offspring of these females do not inherit the instructions to make Vg1 from their mothers, they fail to form the endoderm and mesoderm. This means that the embryos do not have hearts, blood or other internal organs, and they die within three days. Two other groups of researchers have independently reported similar results. The findings reveal that Vg1 is critical for the Nodal signaling pathway to work in zebrafish. Montague and Schier then showed that, in this pathway, Nodal does not activate its receptors on its own. Instead, Nodal must interact with Vg1, and it is this Nodal-Vg1 complex that activates receptors, and instructs cells to become endoderm and mesoderm. Scientists currently use the Nodal signaling pathway to induce human embryonic stem cells growing in the laboratory to become mesoderm and endoderm. As such, these new findings could ultimately help researchers to grow tissues and organs for human patients.