Mechanical feedback defines organizing centers to drive digit emergence

• Published in: Developmental cell 2022-04, Vol.57 (7), p.854-866.e6
• Main Authors: Parada, Carolina, Banavar, Samhita P., Khalilian, Parisa, Rigaud, Stephane, Michaut, Arthur, Liu, Yucen, Joshy, Dennis Manjaly, Campàs, Otger, Gros, Jerome
• Format: Article
• Language: English
• Subjects: Activins; Chondrogenesis; Development Biology; digit; Extremities; Feedback; Gene Expression Regulation, Developmental; Life Sciences; limb development; mechanical feedback; mechanobiology; Morphogenesis; organizing centers; phalanx-forming region/digit crescent; self-organization; tissue mechanics
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2022.03.004

During embryonic development, digits gradually emerge in a periodic pattern. Although genetic evidence indicates that digit formation results from a self-organizing process, the underlying mechanisms are still unclear. Here, we find that convergent-extension tissue flows driven by active stresses underlie digit formation. These active stresses simultaneously shape cartilage condensations and lead to the emergence of a compressive stress region that promotes high activin/p-SMAD/SOX9 expression, thereby defining digit-organizing centers via a mechanical feedback. In Wnt5a mutants, such mechanical feedback is disrupted due to the loss of active stresses, organizing centers do not emerge, and digit formation is precluded. Thus, digit emergence does not result solely from molecular interactions, as was previously thought, but requires a mechanical feedback that ensures continuous coupling between phalanx specification and elongation. Our work, which links mechanical and molecular signals, provides a mechanistic context for the emergence of organizing centers that may underlie various developmental processes. [Display omitted] •Convergent-extension tissue flows underlie digit formation•WNT5A controls tissue flows and the emergence of digit-organizing centers•Active stresses and a fluid-to-solid transition characterize digit formation•A mechanical feedback model captures digit specification and elongation Digit development has been mostly studied from a molecular perspective. In this work, Parada et al. characterize the cellular dynamics and mechanical aspects of digit formation. They find that mechanical cues combine with molecular signals to define the emergence of organizing centers, revealing a coupling between digit specification and elongation.