TY - JOUR
T1 - Self-organized BMP signaling dynamics underlie the development and evolution of digit segmentation patterns in birds and mammals
AU - Grall , Emmanuelle
AU - Feregrino, Christian
AU - Fischer , Sabrina
AU - De Courten, Aline
AU - Sacher, Fabio
AU - Hiscock, Thomas
AU - Tschopp, Patrick
N1 - We wish to thank C. J. Tabin, E. Clark, and J. C. Scoones for a critical reading of the manuscript, M. Luxey, A. Zuniga, and R. Zeller for providing wild-type mouse embryos, M. Wang for help with R, D. Barac for conceptual input on the developmental digit growth series, and D. Ebert, D. Berner, and all members of our groups for useful discussions. Calculations for scRNA-seq analyses were performed at sciCORE (http://scicore.unibas.ch/), scientific computing center at the University of Basel. This work was supported by research funds from UK Research and Innovation [Biotechnology and Biological Sciences Research Council, grant numbers BB/W003619/1 and BB/X511973/1] to T.W.H. and from the Swiss National Science Foundation [SNSF project grant number 310030_189242] and the University of Basel to P.T.
PY - 2024/1/9
Y1 - 2024/1/9
N2 - 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.
AB - 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.
U2 - 10.1073/pnas.2304470121
DO - 10.1073/pnas.2304470121
M3 - Article
SN - 0027-8424
VL - 121
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 2
M1 - 2304470121
ER -