Project Reference: TRG27-PDN-AR1

Project title: Role of mechanotransduction and inter-tissue communication in the control of limb size

Project outline

How developing organs ‘know’ they have reached the right size remains obscure, despite its importance to understanding evolution, cancer and growth disorders. We will explore this question in the vertebrate limb, studying how physical properties related to limb size are interpreted by cells, and how information from inside/outside the limb is coordinated to achieve species-specific limb size and internal proportions.

Developing animals can recover from transient perturbations, reaching the same size as unperturbed individuals. This is known as catch-up growth and implies that stem/progenitor cells ‘know’ how big organs are and should be at each age. The limbs are ideal to study catch-up growth, because they can be manipulated without affecting embryo viability, and are composed of multiple tissues that must grow in coordination. Limb growth is driven by elongation of the long bones via transient cartilage regions at both ends. When one of the cartilage regions is damaged, the spared one compensates for it by giving rise to more bone than normal. This suggests that cartilage cells respond to deviations from a target bone-size-per-age. One possible mechanism is that, as bones elongate, the surrounding tissues become progressively stretched, causing them to release cartilage growth inhibitors. Supporting this idea, it was shown that increased actin-dependent intracellular-tension in the perichondrium—tissue wrapping the cartilage—causes secretion of cartilage growth inhibitors from the perichondrium.

Our novel idea is that perichondrium tension acts as a tally of bone length, such that genetic variants that reduce sensitivity to tension in the perichondrium lead to longer bones. We will test this via a multidisciplinary approach: microsurgery in chicken embryos and mouse genetic models will be used to generate location-specific unilateral growth impairment, to then study subsequent recovery via biophysical, cellular and molecular approaches.

Principal Supervisor

Dr Alberto Rosello-Diez

Email address: ar2204@cam.ac.uk

Department / Partner Institute: Physiology, Development and Neuroscience (PDN)

Website: https://www.pdn.cam.ac.uk/staff/rosello-diez

BBSRC strategic theme

Understanding the rules of life