The Function and Regulation of <i>celsr1a</i> in Skeletal Age-associated Homeostasis and Repair in Zebrafish

The decrease of tissue resiliency with aging is due, in part, to changes in the retention of stem cell/progenitor populations that act to restore and maintain tissue quality with age or injury. In mice, the Celsr1 gene has been identified as a regulator of quiescent stem cells, while in zebrafish, celsr1a mutants demonstrate an essential function in maintaining adult stem cell populations within the highly proliferative tissues of the gut and skin. Here, we investigate the role of celsr1a as a regulator of adult skeletal stem cells and mediator of skeletal homeostasis and repair. We find that celsr1a is essential for maintenance of bone mineral density and volume in adult zebrafish. Using an enhancer screen to identify tissue/cell-specific regulators of celsr1a, we identified enhancers active in specific tissues that reflect the normal expression of celsr1a. We characterized C1a-A an enhancer that is active within stem/progenitor cells of diverse tissues. Consistent with this role, C1a-A marks specific cells in mature skeletal structures of the zebrafish, residing on the endosteal surface of zebrafish vertebrae and fin long-bones. These cells are limited in number and contribute to osteocyte populations within the bony matrix. Using a novel long bone fracture assay in adult zebrafish, we find that celsr1a positive skeletal cells respond to damage and that celsr1a function is essential for fracture healing. Our investigation details an unexpected role of cels1a in skeletal repair and quality with age and highlights a new regulator of stem cell activity in the skeleton.