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Much of the vertebrate skeleton develops from cartilage templates that are progressively remodeled into bone. Lineage tracing studies in mouse suggest that chondrocytes within these templates persist and become osteoblasts, yet the underlying mechanisms of this process and whether chondrocytes can generate other derivatives remain unclear. We find that zebrafish cartilages undergo extensive remodeling and vascularization during juvenile stages to generate fat-filled bones. Growth plate chondrocytes marked by sox10 and col2a1a contribute to osteoblasts, marrow adipocytes, and mesenchymal cells within adult bones. At the edge of the hypertrophic zone, chondrocytes re-enter the cell cycle and express leptin receptor (lepr), suggesting conversion into progenitors. Further, mutation of matrix metalloproteinase 9 (mmp9) results in delayed growth plate remodeling and fewer marrow adipocytes. Our data support Mmp9-dependent growth plate remodeling and conversion of chondrocytes into osteoblasts and marrow adipocytes as conserved features of bony vertebrates., eLife digest Our adult bones are made of a fatty tissue, called marrow, wrapped inside a hard outer layer produced by bone cells. They may appear stiff and unyielding, but our bones are actually dynamic structures. Early in life, most bones start as small ‘templates’ made of another, flexible tissue called cartilage. As the templates grow into adult bones, the cartilage is gradually replaced by bone and fat, but this process is still poorly understood. For example, it is not clear whether cartilage cells simply die and make way for new cells, or instead if they turn into bone and fat cells. To investigate this question, Giovannone, Paul et al. set out to follow the fate of early cartilage cells in zebrafish, and to compare this with what happens in mammals. Zebrafish were chosen because their skeleton and ours develop in similar ways; yet, these animals are much easier to study, in particular because their embryos are transparent. Young cartilage cells were ‘tagged’ with a long-lasting fluorescent protein in genetically engineered zebrafish embryos, and then followed over time. As the embryos started to form bones, the cartilage cells gave rise to bone cells, fat cells, and also potentially adult stem cells within the marrow, which can become other types of cells. This process required a protein called Mmp9, which also helps shape bone development in other organisms, including humans. Defects in how early cartilage templates morph into bone and fat may contribute to dwarfism and other severe conditions. Fully grasping the molecular mechanisms that preside over this complex transition may one day help design drugs to treat skeletal disorders.

Cranial sutures separate the skull bones and house stem cells for bone growth and repair. In Saethre-Chotzen syndrome, mutations in TCF12 or TWIST1 ablate a specific suture, the coronal. This suture forms at a neural-crest/mesoderm interface in mammals and a mesoderm/mesoderm interface in zebrafish. Despite this difference, we show that combinatorial loss of TCF12 and TWIST1 homologs in zebrafish also results in specific loss of the coronal suture. Sequential bone staining reveals an initial, directional acceleration of bone production in the mutant skull, with subsequent localized stalling of bone growth prefiguring coronal suture loss. Mouse genetics further reveal requirements for Twist1 and Tcf12 in both the frontal and parietal bones for suture patency, and to maintain putative progenitors in the coronal region. These findings reveal conservation of coronal suture formation despite evolutionary shifts in embryonic origins, and suggest that the coronal suture might be especially susceptible to imbalances in progenitor maintenance and osteoblast differentiation., eLife digest Some of the most common birth defects involve improper development of the head and face. One such birth defect is called craniosynostosis. Normally, an infant’s skull bones are not fully fused together. Instead, they are held together by soft tissue that allows the baby’s skull to more easily pass through the birth canal. This tissue also houses specialized cells called stem cells that allow the brain and skull to grow with the child. But in craniosynostosis these stem cells behave abnormally, which fuses the skull bones together and prevents the skull and brain from growing properly during childhood. One form of craniosynostosis called Saethre-Chotzen syndrome is caused by mutations in one of two genes that ensure the proper separation of two bones in the roof of the skull. Mice with mutations in the mouse versions of these genes develop the same problem and are used to study this condition. Mouse studies have looked mostly at what happens after birth. Studies looking at what happens in embryos with these mutations could help scientists learn more. One way to do so would be to genetically engineer zebrafish with the equivalent mutations. This is because zebrafish embryos are transparent and grow outside their mother’s body, making it easier for scientists to watch them develop. Now, Teng et al. have grown zebrafish with mutations in the zebrafish versions of the genes that cause Saethre-Chotzen syndrome. In the experiments, imaging tools were used to observe the live fish as they developed. This showed that the stem cells in their skulls become abnormal much earlier than previous studies had suggested. Teng et al. also showed that similar stem cells are responsible for growth of the skull in zebrafish and mice. Babies with craniosynostosis often need multiple, risky surgeries to separate their skull bones and allow their brain and head to grow. Unfortunately, these bones often fuse again because they have abnormal stem cells. Teng et al. provide new information on what goes wrong in these stem cells. Hopefully, this new information will help scientists to one day correct the defective stem cells in babies with craniosynostosis, thus reducing the number of surgeries needed to correct the problem.