Signaling gradients and self-organization during tetrapod digit pattern formation and evolution

Segmentation of digits into individual bones, the so-called phalanges, connected to each other via synovial joints, is a major step during tetrapod limb formation. Thanks to this modular architecture, highly distinct digit morphologies have emerged over the course of vertebrate evolution. During embryogenesis, at the tip of each growing digit, a delicate balance of cell proliferation and cell type specification in a group of progenitor cells, the phalanx-forming region (PFR), needs to be precisely controlled to ensure proper digit patterning. The TGF-beta superfamily, including signaling through Bone morphogenetic proteins (BMPs), has been implicated in this process. However, the exact molecular mechanisms underlying the specification and diversification of digit patterns remain unclear.
This PhD thesis aims to decipher how molecular cues are integrated and interpreted, to orchestrate cell fate decisions at the PFR into either joint or phalanx precursors, and to what extent these mechanisms can be modified on an evolutionary timescale, to generate novel digit morphologies.
For this, we are using the chicken foot as a model, in which all digits are morphologically different. To decipher the underlying patterning mechanisms, we produced morphological growth and signaling dynamics data over the course of chicken digit development. Moreover, by combining this quantitative data with mathematical modeling, we tried to approximate digit patterning in silico. Indeed, this allowed us to formulate a Turing-like model based on BMP signaling modulators interactions that can explain the emergence of a repetitive phalanx-joint pattern.
In addition, to understand how signals received by the PFR are interpreted to allow for cell fate decisions control of the joint and phalanx precursors shaping a digit, data describing the transcriptional dynamics of chicken digit patterning was produced and analyzed. To this aim, we used single-cell RNA-sequencing, pseudotime analyses and experimental embryology to define candidate regulators of phalanx versus joint cell fate decisions.
Collectively, the present work aims to contribute to our understanding of the mechanisms underlying tetrapod digit patterns specification and diversification.