Abstract
ABSTRACTOsteoblasts arise from bone-surrounding connective tissue containing tenocytes and fibroblasts. Lineages of these cell populations and mechanisms of their differentiation are not well understood. Screening enhancer-trap lines of zebrafish allowed us to identify Ebf3 as a transcription factor marking tenocytes and connective tissue cells in skeletal muscle of embryos. Knockout of Ebf3 in mice had no effect on chondrogenesis but led to sternum ossification defects as a result of defective generation of Runx2+ pre-osteoblasts. Conditional and temporal Ebf3 knockout mice revealed requirements of Ebf3 in the lateral plate mesenchyme cells (LPMs), especially in tendon/muscle connective tissue cells, and a stage-specific Ebf3 requirement at embryonic day 9.5-10.5. Upregulated expression of connective tissue markers, such as Egr1/2 and Osr1, increased number of Islet1+ mesenchyme cells, and downregulation of gene expression of the Runx2 regulator Shox2 in Ebf3-deleted thoracic LPMs suggest crucial roles of Ebf3 in the onset of lateral plate mesoderm differentiation towards osteoblasts forming sternum tissues.
Highlights
The sternum protects the heart and lungs in vertebrates and constitutes the most ventral part of the thoracic skeleton
Runx1 and Runx2 cooperatively regulate sternal morphogenesis and the commitment of lateral plate mesenchyme cells (LPMs) to differentiate into sternal chondrocytes ; sternum tissue has been found to be completely absent in Prx1-Cre-induced Runx1/Runx2 double-KO mice (Kimura et al, 2010)
E9.5 approximately corresponds to the earliest stage of limb bud formation, whereas E10.5 is the stage when Runx2 starts to be expressed in a proportion of the LPMs along the rib cage
Summary
The sternum protects the heart and lungs in vertebrates and constitutes the most ventral part of the thoracic skeleton. The evolution of the sternum highlights its crucial role in forelimb locomotion as a connecting site for the pectoral-muscle tendons (Chen, 1952; Bickley and Logan, 2014). Evidence suggests that osteoblasts differentiate from mesenchymal stem cells (MSCs) that possess the potential to differentiate into osteoblasts, chondrocytes, tenocytes, and perhaps even muscle connective tissue (MCT) cells, fibroblastic cells and adipocytes (Caplan, 1991). The cellular hierarchies of mesenchymal differentiation into osteoblasts and MCT cells have not been delineated very well
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