Self- organized BMP signaling dynamics underlie the development and evolution of digit segmentation patterns in birds and mammals

• 成果类型: Article
• 署名作者: Grall, Emmanuelle; Feregrino, Christian; Fischer, Sabrina; De Courten, Aline; Sacher, Fabio; Hiscock, Tom W.; Tschopp, Patrick
• 署名单位: University of Basel; University of Aberdeen; Helmholtz Association; Max Delbruck Center for Molecular Medicine
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8905
• DOI: 10.1073/pnas.2304470121
• 发表日期: 2024-01-09
• 关键词: joint formation; tgf-beta; limb; bone; noggin; morphogenesis; mutations; gdf5; chondrogenesis; hyperphalangy

摘要

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 dynam-ics 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.