RT Journal Article SR Electronic T1 Growth orientations, rather than heterogeneous growth rates, dominate jaw joint morphogenesis in the larval zebrafish JF bioRxiv FD Cold Spring Harbor Laboratory SP 2022.01.13.476166 DO 10.1101/2022.01.13.476166 A1 Josepha Godivier A1 Elizabeth A. Lawrence A1 Mengdi Wang A1 Chrissy L. Hammond A1 Niamh C. Nowlan YR 2022 UL http://biorxiv.org/content/early/2022/01/13/2022.01.13.476166.abstract AB In early limb embryogenesis, synovial joints acquire specific shapes which determine joint motion and function. The process by which the opposing cartilaginous joint surfaces are moulded into reciprocal and interlocking shapes, called joint morphogenesis, is one of the least understood aspect of joint formation and the cell-level dynamics underlying it are yet to be unravelled. In this research, we quantified key cellular dynamics involved in growth and morphogenesis of the zebrafish jaw joint and synthesised them in a predictive computational simulation of joint development. Cells in larval zebrafish jaw joints labelled with cartilage markers were tracked over a forty-eight hour time window using confocal imaging. Changes in distance and angle between adjacent cell centroids resulting from cell rearrangement, volume expansion and extracellular matrix (ECM) deposition were measured and used to calculate the rate and direction of local tissue deformations. We observed spatially and temporally heterogeneous growth patterns with marked anisotropy over the developmental period assessed. There was notably elevated growth at the level of the retroarticular process of the Meckel’s cartilage, a feature known to undergo pronounced shape changes during zebrafish development. Analysis of cell dynamics indicated a dominant role for cell volume expansion in growth, with minor influences from ECM volume increases and cell intercalation. Cell proliferation in the joint was minimal over the timeframe of interest. Synthesising the dynamic cell data into a finite element model of jaw joint development resulted in accurate shape predictions. Our biofidelic computational simulation demonstrated that zebrafish jaw joint growth can be reasonably approximated based on cell positional information over time, where cell positional information derives mainly from cell orientation and cell volume expansion. By modifying the input parameters of the simulation, we were able to assess the relative contributions of heterogeneous growth rates and of growth orientation. The use of uniform rather than heterogeneous growth rates only minorly impacted the shape predictions whereas isotropic growth fields resulted in altered shape predictions. The simulation results suggest that growth anisotropy is the dominant influence on joint growth and morphogenesis. This study addresses the gap of the cellular processes underlying joint morphogenesis, with implications for understanding the aetiology of developmental joint disorders such as developmental dysplasia of the hip and arthrogryposis.Competing Interest StatementThis research was funded by an Anatomical Society PhD studentship to J.G.. C.L.H. was funded by Versus Arthritis Fellowship 29137. E.L. was funded by a Wellcome Trust Dynamic Cell PhD studentship. M.W. was funded by the China Scholarship Council.