Nodal is a short-range morphogen with activity that spreads through a relay mechanism in human gastruloids.
Nodal is a short-range morphogen with activity that spreads through a relay mechanism in human gastruloids.
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DOI：
10.1038/s41467-022-28149-3
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发表时间：
2022-01-25
影响因子：
16.6
通讯作者：
Warmflash A
中科院分区：
文献类型：
--
作者：
Liu L;Nemashkalo A;Rezende L;Jung JY;Chhabra S;Guerra MC;Heemskerk I;Warmflash A
形态发生素是在发育过程中传递位置信息并决定细胞命运的信号分子。虽然异位表达模式生物表明，形态梯度的形式通过扩散，很少有人知道形态梯度是如何创建和解释哺乳动物胚胎发生过程中，由于测量内源性形态水平和观察子宫内的发展相结合的困难。在这里，我们利用人胃类模型可视化内源性Nodal蛋白在活细胞中，在指定的胚层。我们表明，Nodal是非常短的范围，使Nodal蛋白质是有限的直接邻近的源细胞。Nodal活性通过中继机制传播，其中Nodal产生诱导邻近细胞转录Nodal。我们进一步表明，节点的抑制剂左撇子，而生化能够远程扩散，也采取行动，局部控制节点的传播时间，因此在图案化过程中的中胚层分化。我们的研究建立了一个组织模式的激活剂-抑制剂对。研究哺乳动物发育中形态梯度的形成和接受是具有挑战性的。在这里，作者用人类类胃体细胞表明，活细胞中的Nodal活性通过中继机制传播，其时间由Lefty局部控制，这决定了中胚层分化的时间。
Morphogens are signaling molecules that convey positional information and dictate cell fates during development. Although ectopic expression in model organisms suggests that morphogen gradients form through diffusion, little is known about how morphogen gradients are created and interpreted during mammalian embryogenesis due to the combined difficulties of measuring endogenous morphogen levels and observing development in utero. Here we take advantage of a human gastruloid model to visualize endogenous Nodal protein in living cells, during specification of germ layers. We show that Nodal is extremely short range so that Nodal protein is limited to the immediate neighborhood of source cells. Nodal activity spreads through a relay mechanism in which Nodal production induces neighboring cells to transcribe Nodal. We further show that the Nodal inhibitor Lefty, while biochemically capable of long-range diffusion, also acts locally to control the timing of Nodal spread and therefore of mesoderm differentiation during patterning. Our study establishes a paradigm for tissue patterning by an activator-inhibitor pair. Studying morphogen gradient formation and reception in mammalian development is challenging. Here, the authors show with human gastruloids that Nodal activity in live cells spreads via a relay mechanism with timing that is locally controlled by Lefty, which dictates mesoderm differentiation timing.
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