PT  - JOURNAL ARTICLE
AU  - Alberto Roselló-Díez
AU  - Linda Madisen
AU  - Sébastien Bastide
AU  - Hongkui Zeng
AU  - Alexandra L. Joyner
TI  - Cell-nonautonomous local and systemic responses to cell arrest enable long-bone catch-up growth in developing mice
AID  - 10.1101/218487
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 218487
4099  - http://biorxiv.org/content/early/2017/12/23/218487.short
4100  - http://biorxiv.org/content/early/2017/12/23/218487.full
AB  - Catch-up growth after insults to growing organs is paramount to achieving robust body proportions. In fly larvae, local injury is followed by local and systemic compensatory mechanisms that allow damaged tissues to regain proportions with other tissues. In vertebrates, local catch-up growth has been described after transient reduction of bone growth, but the underlying cellular responses are controversial. We developed an approach to study catch-up growth in foetal mice by inducing mosaic expression of the cell cycle suppressor p21 in the cartilage cells (chondrocytes) that drive long bone elongation. By specifically targeting the left hindlimb, the right limb served as an internal control. Strikingly, left-right limb symmetry was not altered, revealing deployment of compensatory mechanisms. Above a certain threshold of insult, an orchestrated response was triggered involving local enhancement of bone growth and systemic growth reduction that ensured body proportions were maintained. The local response entailed hyper-proliferation of spared left-limb chondrocytes that was associated with reduced chondrocyte density. The systemic effect involved impaired placental IGF signalling and function, revealing bone-placenta communication. Thus, vertebrates, much like invertebrates, can mount coordinated local and systemic responses to developmental insults to ensure normal body proportions are maintained.