Key to development of a healthy individual is precise scaling of growth of all the organs, as well as tissues within each organ. In order to develop therapies for congenital and environmentally induced diseases that result from disproportionate growth of organs, we must identify the pathways and cellular behaviors that act within and between organs to ensure coordinated growth. However, few studies have systematically addressed the genes and processes that ensure tissue scaling. We hypothesize that the peripheral nervous system (PNS), which interconnects all organs and communicates with the central nervous system, plays an important role in coordination of growth control. The paired limbs provide an excellent model to study growth regulation at multiple levels, including inter-organ coordination to ensure similar proportions of each limb are attained following temporary disruption of growth of one limb. A major obstacle to studies of organ growth coordination is a lack of animal models in which growth can be transiently perturbed. We propose to establish a robust mouse model that will enable future studies of how growth is coordinated between the left and right (LR) limbs, and test whether the PNS regulates LR symmetry. Of direct medical relevance to this model, Leg Length Discrepancy (LLD) in which the two lower limbs are >2cm different in length is prevalent in children, and is associated with abnormal gait, scoliosis and degenerative joint disease. Studies using mouse models to identify the factors that regulate limb symmetry should enable development of non-surgical methods for unilateral growth regulation in children.
Our specific aims are:
Aim 1. To develop a mouse model of LLD using intersectional genetics to alter chondrocyte growth in left limbs and to test whether different limb perturbations (cell death and altered growth rates) lead to a similar degree of recovery of symmetry.
Aim 2. Test the role of the PNS in LR leg symmetry and identify potential growth regulatory genes using a transcriptome comparison of long bone growth plates undergoing recovery to that in paired unaffected limbs. Our new models will provide the basis for mechanistic studies to identify molecules involved in the inter-tissue and -organ communication responsible for proper scaling and that could be used for therapies.
Leg Length Discrepancy (LLD) occurs frequently in children, with infections being a primary cause, but trauma and tumors also contribute, as well as congenital defects of largely unknown genetic origin. LLD is often treated by bone lengthening using distraction osteogenesis, which causes postoperative complications. We will develop a mouse model of LLD to enable research aimed at identifying the factors that regulate limb symmetry and development of non-surgical methods for unilateral growth regulation in children.
| Roselló-Díez, Alberto; Madisen, Linda; Bastide, Sébastien et al. (2018) Cell-nonautonomous local and systemic responses to cell arrest enable long-bone catch-up growth in developing mice. PLoS Biol 16:e2005086 |
| Roselló-Díez, Alberto; Stephen, Daniel; Joyner, Alexandra L (2017) Altered paracrine signaling from the injured knee joint impairs postnatal long bone growth. Elife 6: |
| Joyner, Alexandra L (2016) From Cloning Neural Development Genes to Functional Studies in Mice, 30 Years of Advancements. Curr Top Dev Biol 116:501-15 |
| Roselló-Díez, Alberto; Joyner, Alexandra L (2015) Regulation of Long Bone Growth in Vertebrates; It Is Time to Catch Up. Endocr Rev 36:646-80 |
