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Forcing cell differentiation at the fingertips

An interplay between tissue mechanics and molecular signaling enables the emergence of digits.

Looking at one's own hand, it is obvious that its function relies both on its shape, comprising elongated articulated fingers, but also on the rigidity of the bones that compose it. While both aspects, the shaping of the digit and the differentiation of cells into bone, must be tightly coupled during embryonic development to ensure the formation of a fully functioning hand at birth, we know little about how such coupling operates.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Left: Mouse forelimb expressing a GFP transgene reporting Sox9 expression (bottom) with a focus on the forming digit expressing a membrane tdTomato transgene (top).  The magenta region highlights digit organizing centers where compressive forces enable the emergence of phalanges via Sox9 expression. 

Right: Mouse forelimb expressing a GFP transgene reporting Sox9 expression (bottom) with a focus on the forming digit  expressing a membrane tdTomato transgene (top). The movie reveals the cell movements that couple digit elongation and differentiation.

Thanks to a collaborative HFSP Early Career Grant, the labs of Jerome Gros (Institut Pasteur, Paris, France) and Otger Campas (Physics of life Excellence Cluster, TU Dresden, Germany) combined their expertise in pattern formation and in the physics of embryonic development to develop interdisciplinary approaches to addresses this question. First, they established live imaging conditions to capture the dynamics of digit formation in mouse embryos. They identified the cellular behavior (rearrangements), tissue flows (convergent-extension) as well as the molecular signaling (Wnt5a) responsible for the elongation of the digits. In a mouse mutant for Wnt5a, the tissue flows are impaired and the elongation of all skeletal elements of the limb is perturbed, precluding the emergence of digits despite the normal growth of the hand plate. Combining computer simulations, in situ force measurements and functional perturbations, the team provides evidence that a mechanical feedback on molecular signaling acting at the tip of the developing digit is responsible for the control of both the shape and the differentiation of the phalangeal bone. 

Such mechano-chemical feedback provides a simple mechanism for the emergence of digits but also for their sustained formation and concomitant elongation.  Furthermore, such feedback could also underlie the formation of various structures and organs during development.  

HFSP award information

Research Grant - Early Career (RGY0067/2015): Mechanical control of progenitor cell renewal and differentiation during vertebrate limb formation

Principal investigator: Jérôme Gros, Institut Pasteur, Paris, France
Co-investigator: Otger Campas, University of California, Santa Barbara, USA (nationality: Spain)

Reference

Mechanical feedback defines organizing centers to drive digit emergence. 
Parada, C., Banavar, S.P., Khalilian, P., Rigaud, S., Michaut, A., Liu, Y., Joshy, D.M., Campàs, O., and Gros, J. (2022).  Dev. Cell 57, 854-866.e6.

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Reference

Mechanical feedback defines organizing centers to drive digit emergence. 
Parada, C., Banavar, S.P., Khalilian, P., Rigaud, S., Michaut, A., Liu, Y., Joshy, D.M., Campàs, O., and Gros, J. (2022).  Dev. Cell 57, 854-866.e6.