Bone and muscle are coupled through developmental, mechanical, paracrine, and autocrine signals. Genetic variants at the CPED1-WNT16 locus are dually associated with bone- and muscle-related traits. While Wnt16 is necessary for bone mass and strength, this fails to explain pleiotropy at this locus. Here, we show wnt16 is required for spine and muscle morphogenesis in zebrafish. In embryos, wnt16 is expressed in dermomyotome and developing notochord, and contributes to larval myotome morphology and notochord elongation. Later, wnt16 is expressed at the ventral midline of the notochord sheath, and contributes to spine mineralization and osteoblast recruitment. Morphological changes in wnt16 mutant larvae are mirrored in adults, indicating that wnt16 impacts bone and muscle morphology throughout the lifespan. Finally, we show that wnt16 is a gene of major effect on lean mass at the CPED1-WNT16 locus. Our findings indicate that Wnt16 is secreted in structures adjacent to developing bone (notochord) and muscle (dermomyotome) where it affects the morphogenesis of each tissue, thereby rendering wnt16 expression into dual effects on bone and muscle morphology. This work expands our understanding of wnt16 in musculoskeletal development and supports the potential for variants to act through WNT16 to influence bone and muscle via parallel morphogenetic processes.

Identifying the mechanisms by which genetic variants exert pleiotropic effects on muscle and bone is a promising strategy to reveal molecular pathways that stimulate coupled bone and muscle growth, and which can be targeted to treat osteoporosis and sarcopenia simultaneously. Previously, it has been shown that genetic variants at the CPED1-WNT16 locus have pleiotropic effects on bone mineral density (BMD) and lean tissue mass in humans. While it is known that WNT16 is required for normal bone mass, our current functional understanding of WNT16 cannot account for dual effects on bone and lean mass at this locus. Using single cell analysis, microCT imaging, and genetic approaches, we reveal that wnt16 exerts pleiotropic effects on bone and lean tissue in zebrafish. We show an early influence of wnt16 on axial bone and lean tissue during skeletogenesis, and provide evidence that wnt16+ cells are myogenic precursors during embryonic development. We also show that wnt16 is a gene of major effect at the CPED1-WNT16 locus. Our findings indicate a critical function for wnt16 in muscle and lean tissue development and support WNT16 as the principal gene driving pleiotropic effects on bone and lean mass at this locus.

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