Cell-nonautonomous local and systemic responses to cell arrest enable long-bone catch-up growth

Background

Lewis Wolpert, among others, has noted that it is remarkable how paired organs, such as the limbs, grow in precise symmetry (see https://doi.org/10.1371/journal.pbio.1000477). Even more remarkable is that this coordination is restored upon unilateral growth insult of the limb, so that the left and right limbs end up with similar sizes at birth. The study of Alberto Rosello-Diez, Alexandra Joyner and colleagues provides new insight into how this happens.

Key results

The authors use a clever genetic approach to arrest cell proliferation of a fraction of chrondrocytes within the left limb of mouse embryos. This caused compensatory overproliferation of the non-arrested neighboring chrondrocytes. Remarkably, this perturbation also affected growth of the rest of the body, causing the right limb to become 10% smaller than in control embryos. Thus, both intrinsic and extrinsic mechanisms regulate limb growth. The approach opens a new way forward to investigating what these mechanisms are at the molecular level. The authors link the limb-intrinsic compensation to sensing cell density within the growth plate, and the systemic effect – to IGF secreted by the placenta.

Open questions

Further studies will be needed to find out: what is the “alarm” signal sent by the perturbed limb? Is the same signal involved in the intrinsic and systemic mechanisms? How do mechanical vs biochemical signals contribute to proliferation control in this system?

preLighter Natalie Dye has also highlighted this preprint – check out her highlight here.

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