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

Abstract

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.

Periodic pattern formation during embryonic development

“…Firstly, models using two separate Turing patterning systems, one which defines dots, and one stripes, were shown in silico to be capable of explaining joint number, position, and orientation across various vertebrate species. Secondly, a recent paper [ 84 ] combining experimental data and in silico modelling suggested that a BMP-based Turing system may be behind these patterning events.…”

Single-cell profiling of penta- and tetradactyl mouse limb buds identifies mesenchymal progenitors controlling digit numbers and identities

“…28-30 The activity of the PFR regulates the number and length of phalanges formed, which is the main morphological feature of digit identities in addition to their AP positions. 29,31 Currently there is a significant knowledge gap in understanding how the early and direct specification of posterior digits by SHH 3 is linked to establishment of the definitive digit pattern and identities during autopod development. This early specification must trigger molecular changes in target limb bud mesenchymal progenitor (LMP) cells that are propagated during progression of limb bud outgrowth and autopod development.…”