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胚胎发育过程中内源性视黄酸梯度的可视化。

Visualization of an endogenous retinoic acid gradient across embryonic development.

机构信息

Laboratory for Cell Function Dynamics, Brain Science Institute, RIKEN, 2-1 Hirosawa, Wako-city, Saitama 351-0198, Japan.

出版信息

Nature. 2013 Apr 18;496(7445):363-6. doi: 10.1038/nature12037. Epub 2013 Apr 7.

Abstract

In vertebrate development, the body plan is determined by primordial morphogen gradients that suffuse the embryo. Retinoic acid (RA) is an important morphogen involved in patterning the anterior-posterior axis of structures, including the hindbrain and paraxial mesoderm. RA diffuses over long distances, and its activity is spatially restricted by synthesizing and degrading enzymes. However, gradients of endogenous morphogens in live embryos have not been directly observed; indeed, their existence, distribution and requirement for correct patterning remain controversial. Here we report a family of genetically encoded indicators for RA that we have termed GEPRAs (genetically encoded probes for RA). Using the principle of fluorescence resonance energy transfer we engineered the ligand-binding domains of RA receptors to incorporate cyan-emitting and yellow-emitting fluorescent proteins as fluorescence resonance energy transfer donor and acceptor, respectively, for the reliable detection of ambient free RA. We created three GEPRAs with different affinities for RA, enabling the quantitative measurement of physiological RA concentrations. Live imaging of zebrafish embryos at the gastrula and somitogenesis stages revealed a linear concentration gradient of endogenous RA in a two-tailed source-sink arrangement across the embryo. Modelling of the observed linear RA gradient suggests that the rate of RA diffusion exceeds the spatiotemporal dynamics of embryogenesis, resulting in stability to perturbation. Furthermore, we used GEPRAs in combination with genetic and pharmacological perturbations to resolve competing hypotheses on the structure of the RA gradient during hindbrain formation and somitogenesis. Live imaging of endogenous concentration gradients across embryonic development will allow the precise assignment of molecular mechanisms to developmental dynamics and will accelerate the application of approaches based on morphogen gradients to tissue engineering and regenerative medicine.

摘要

在脊椎动物的发育过程中,形态发生梯度决定了胚胎的体节模式。视黄酸(RA)是一种重要的形态发生素,参与了包括后脑和轴旁中胚层在内的结构的前-后轴模式形成。RA 可以远距离扩散,其活性通过合成和降解酶来限制空间。然而,活胚胎中内源性形态发生素的梯度尚未被直接观察到;事实上,它们的存在、分布和对正确模式形成的要求仍然存在争议。在这里,我们报告了一类我们称之为 GEPRAs(RA 的遗传编码探针)的遗传编码 RA 指示剂。我们利用荧光共振能量转移的原理,将 RA 受体的配体结合结构域设计为分别包含青色发射和黄色发射荧光蛋白的荧光共振能量转移供体和受体,以可靠地检测环境中的游离 RA。我们创建了三种对 RA 具有不同亲和力的 GEPRAs,能够对生理 RA 浓度进行定量测量。在原肠胚和体节形成阶段对斑马鱼胚胎进行活细胞成像,揭示了胚胎中存在一种 RA 内源性浓度呈双尾源-汇排列的线性梯度。对观察到的线性 RA 梯度的建模表明,RA 扩散的速度超过了胚胎发生的时空动态,从而保持了稳定性。此外,我们使用 GEPRAs 结合遗传和药理学扰动,解决了在后脑形成和体节形成过程中 RA 梯度结构的竞争假说。对胚胎发育过程中内源性浓度梯度的实时成像将使我们能够精确地将分子机制分配到发育动力学中,并加速基于形态发生素梯度的方法在组织工程和再生医学中的应用。

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