Self-organized BMP signaling dynamics underlie the development and evolution of digit segmentation patterns in birds and mammals.
Self-organized BMP signaling dynamics underlie the development and evolution of digit segmentation patterns in birds and mammals.
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DOI：
10.1073/pnas.2304470121
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发表时间：
2024-01-09
影响因子：
11.1
通讯作者：
Tschopp, Patrick
中科院分区：
文献类型：
--
作者：
Grall, Emmanuelle;Feregrino, Christian;Fischer, Sabrina;De Courten, Aline;Sacher, Fabio;Hiscock, Tom W.;Tschopp, Patrick
四足动物的足趾被分割成单独的骨骼，即趾骨，趾骨通过滑膜关节连接，趾骨的数量和大小变化产生不同的肢体形态。给定的范围内的关节数在一个给定的手指从1在人类的拇指超过10在某些物种的鲸鱼的第二个数字，它已被推测，自组织机制可能是这些重复的分割模式的启动。在这里，使用单细胞分子分析，在体内生长系列，和数学建模，我们发现了一个自组织图灵系统，确定数字分割。这些结果对我们理解手指的图案及其进化的多样性，以及人类先天性手脚畸形的病因学具有重要意义。重复模式的滑膜关节是一个高度保守的功能，关节的数量和位置的变化，导致不同的数字形态和肢体功能的四足动物分支。在长趾肢的发育过程中，关节在不断生长的趾线内反复形成，因为远端祖细胞的群体交替指定关节和指骨细胞的命运以将趾分割成不同的元素。虽然许多分子途径与这种命运选择有关，但仍不清楚它们如何引起重复模式。在这里，使用单细胞RNA测序和空间基因表达谱，我们研究了体内指间关节规范的转录动力学。结合数学建模，我们预测，BMP信号通路内的配体GDF5，抑制剂NOGGIN，和细胞内效应pSMAD之间的相互作用，导致形成周期性关节模式的自组织图灵系统。我们的模型能够概括在体内观察到的时空基因表达动态，以及BMP通路扰动引起的表型数字畸形。通过对比两个形态不同的数字在体内形态测量的模拟，我们展示了信号参数和生长动力学的变化如何导致指骨的大小和数量的变化。总之，我们的研究结果揭示了一种自组织机制，该机制支撑了数字分割及其可进化性，更广泛地说，说明了基于单一分子途径的图灵系统如何在各种生物体中产生复杂的重复模式。
Tetrapod digits are segmented into individual bones, the phalanges, which are connected by synovial joints, with variations to phalanx number and size generating diverse limb morphologies. Given the range of joint numbers within a given digit—from 1 in the human thumb to over 10 in the second digit of certain species of whale—it has been speculated that self-organizing mechanisms may underlie the initiation of these repetitive segmentation patterns. Here, using single-cell molecular profiling, in vivo growth series, and mathematical modeling, we uncover a self-organizing Turing system that determines digit segmentation. These results have implications for our understanding of amniote digit patterning and its evolutionary diversification, as well as for the etiology of human congenital malformations of the hands and feet. Repeating patterns of synovial joints are a highly conserved feature of articulated digits, with variations in joint number and location resulting in diverse digit morphologies and limb functions across the tetrapod clade. During the development of the amniote limb, joints form iteratively within the growing digit ray, as a population of distal progenitors alternately specifies joint and phalanx cell fates to segment the digit into distinct elements. While numerous molecular pathways have been implicated in this fate choice, it remains unclear how they give rise to a repeating pattern. Here, using single-cell RNA sequencing and spatial gene expression profiling, we investigate the transcriptional dynamics of interphalangeal joint specification in vivo. Combined with mathematical modeling, we predict that interactions within the BMP signaling pathway—between the ligand GDF5, the inhibitor NOGGIN, and the intracellular effector pSMAD—result in a self-organizing Turing system that forms periodic joint patterns. Our model is able to recapitulate the spatiotemporal gene expression dynamics observed in vivo, as well as phenocopy digit malformations caused by BMP pathway perturbations. By contrasting in silico simulations with in vivo morphometrics of two morphologically distinct digits, we show how changes in signaling parameters and growth dynamics can result in variations in the size and number of phalanges. Together, our results reveal a self-organizing mechanism that underpins amniote digit segmentation and its evolvability and, more broadly, illustrate how Turing systems based on a single molecular pathway may generate complex repetitive patterns in a wide variety of organisms.
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影响因子：
64.5
作者：
Antebi YE;Linton JM;Klumpe H;Bintu B;Gong M;Su C;McCardell R;Elowitz MB
通讯作者：
Elowitz MB
DOI：
10.1073/pnas.0504750102
发表时间：
2005-10-11
影响因子：
11.1
作者：
Akiyama, H;Kim, JE;de Crombrugghe, B
通讯作者：
de Crombrugghe, B
影响因子：
4.6
作者：
Hilton, MJ;Tu, XL;Long, FX
通讯作者：
Long, FX
影响因子：
5.8
作者：
Angerer, Philipp;Haghverdi, Laleh;Buettner, Florian
通讯作者：
Buettner, Florian
影响因子：
56.9
作者：
Dahn, RD;Fallon, JF
通讯作者：
Fallon, JF