Hecate/Grip2a acts to reorganize the cytoskeleton in the symmetry-breaking event of embryonic axis induction.
Hecate/Grip2a acts to reorganize the cytoskeleton in the symmetry-breaking event of embryonic axis induction.
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DOI：
10.1371/journal.pgen.1004422
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发表时间：
2014-06
期刊：
影响因子：
4.5
通讯作者：
Pelegri F
中科院分区：
文献类型：
--
作者：
Ge X;Grotjahn D;Welch E;Lyman-Gingerich J;Holguin C;Dimitrova E;Abrams EW;Gupta T;Marlow FL;Yabe T;Adler A;Mullins MC;Pelegri F
母体纯合性为三个独立的突变hecate等位基因的结果，在胚胎的背组织者基因的表达减少和缺陷的形成dorsoanterior结构。一种定位克隆方法将所有hecate突变识别为影响同一基因的终止密码子，揭示了hecate编码谷氨酸受体相互作用蛋白2a（Grip 2a），该蛋白含有多个PDZ结构域，已知与膜相关因子（包括Wnt）相互作用。信号通路。我们发现，grip2a mRNA定位于植物极的卵母细胞和早期胚胎，并在卵激活这mRNA转移到一个偏离中心的植物位置对应于先前提出的硬骨鱼皮质旋转。hecate突变体在植物皮层的微管排列和成束方面显示出缺陷，这导致wnt 8a mRNA的不对称运动以及驱动蛋白相关的货物衔接子Syntabulin的锚定方面的缺陷。我们还发现，虽然植物信号的短程转移在hecate突变胚胎的影响，这些突变体表现出正常的远程，动物定向易位的皮质注射的背珠发生在卵黄皮质的横向区域。此外，我们表明，这种动物定向运动沿着侧皮质不限于一个单一的弧对应的前景背区，但发生在多个dendional弧，甚至在相反的地区的胚胎。总之，我们的研究结果揭示了Grip2a功能在植物皮层微管的重组和捆绑中的作用，以介导与硬骨鱼皮层旋转相对应的破坏性短距离移位。轻微的不对称性实现了这一定向过程随后放大了一般的皮质动物定向运输机制，既不依赖于hecate功能，也不限于前瞻性的背轴。动物发育中最早和最关键的事件之一是胚胎背轴的建立。在两栖动物和鱼类中，这一事件取决于所谓的“背决定簇”从卵的一个区域（位于卵母细胞核所在位置的相反极）向轴诱导部位的运输。在那里，背侧决定子激活Wnt信号通路，这反过来触发背侧基因表达。背侧决定簇转运是由微管组成的细胞网络的重组介导的。我们确定，hecate，一个斑马鱼基因在卵子形成过程中的活跃，是胚胎轴诱导所必需的，是需要在这个微管重组的早期步骤。我们发现，hecate对应于谷氨酸受体相互作用蛋白2a，它参与其他动物系统的Wnt为基础的途径。我们还表明，微管重组依赖于hecate的结果在一个微妙的破膜事件，随后成为放大的一个更一般的运输过程独立的hecate功能。我们的数据揭示了谷氨酸受体相互作用蛋白2a，Wnt信号传导和轴诱导之间的新联系，并强调了发育早期微小变化转化为胚胎整体变化的基本机制。
Maternal homozygosity for three independent mutant hecate alleles results in embryos with reduced expression of dorsal organizer genes and defects in the formation of dorsoanterior structures. A positional cloning approach identified all hecate mutations as stop codons affecting the same gene, revealing that hecate encodes the Glutamate receptor interacting protein 2a (Grip2a), a protein containing multiple PDZ domains known to interact with membrane-associated factors including components of the Wnt signaling pathway. We find that grip2a mRNA is localized to the vegetal pole of the oocyte and early embryo, and that during egg activation this mRNA shifts to an off-center vegetal position corresponding to the previously proposed teleost cortical rotation. hecate mutants show defects in the alignment and bundling of microtubules at the vegetal cortex, which result in defects in the asymmetric movement of wnt8a mRNA as well as anchoring of the kinesin-associated cargo adaptor Syntabulin. We also find that, although short-range shifts in vegetal signals are affected in hecate mutant embryos, these mutants exhibit normal long-range, animally directed translocation of cortically injected dorsal beads that occurs in lateral regions of the yolk cortex. Furthermore, we show that such animally-directed movement along the lateral cortex is not restricted to a single arc corresponding to the prospective dorsal region, but occur in multiple meridional arcs even in opposite regions of the embryo. Together, our results reveal a role for Grip2a function in the reorganization and bundling of microtubules at the vegetal cortex to mediate a symmetry-breaking short-range shift corresponding to the teleost cortical rotation. The slight asymmetry achieved by this directed process is subsequently amplified by a general cortical animally-directed transport mechanism that is neither dependent on hecate function nor restricted to the prospective dorsal axis. One of the earliest and most crucial events in animal development is the establishment of the embryonic dorsal axis. In amphibians and fish, this event depends on the transport of so-called “dorsal determinants” from one region of the egg, at the pole opposite from the site where the oocyte nucleus lies, towards the site of axis induction. There, the dorsal determinant activates the Wnt signaling pathway, which in turn triggers dorsal gene expression. Dorsal determinant transport is mediated by the reorganization of a cellular network composed of microtubules. We determine that hecate, a zebrafish gene active during egg formation that is essential for embryonic axis induction, is required for an early step in this microtubule reorganization. We find that hecate corresponds to glutamate receptor interacting protein 2a, which participates in other animal systems in Wnt-based pathways. We also show that the microtubule reorganization dependent on hecate results in a subtle symmetry-breaking event that subsequently becomes amplified by a more general transport process independent of hecate function. Our data reveal new links between glutamate receptor interacting protein 2a, Wnt signaling and axis induction, and highlights basic mechanisms by which small changes early in development translate into global changes in the embryo.
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