Switching of Sox9 expression during musculoskeletal system development

Abstract

The musculoskeletal system, which comprises muscles, tendons, and bones, is an efficient tissue complex that coordinates body movement and maintains structural stability. The process of its construction into a single functional and complex organization is unclear. SRY-box containing gene 9 (Sox9) is expressed initially in pluripotent cells and subsequently in ectodermal, endodermal, and mesodermal derivatives. This study investigated how Sox9 controls the development of each component of the musculoskeletal system. Sox9 was expressed in MTJ, tendon, and bone progenitor cells at E13 and in bone at E16. We detected Sox9 expression in muscle progenitor cells using doubletransgenic mice and myoblastic cell lines. However, we found no Sox9 expression in developed muscle. A decrease in Sox9 expression in muscle-associated connective tissues, tendons, and bones led to hypoplasia of the cartilage and its attachment to tendons and muscle. These results showed that switching on Sox9 expression in each component (muscle, tendon, and bone) is essential for the development of the musculoskeletal system. Sox9 is expressed in not only tendon and bone progenitor cells but also muscle progenitor cells, and it controls musculoskeletal system development. The musculoskeletal system comprises muscles, tendons, and bones. It is an efficient tissue complex that coordinates body movement and maintains structural stability 1. This requires effective linkage of muscles to bones. Many studies have reported the development of each component of the musculoskeletal system, but the process of its construction into a single functional and complex organization is unclear. Muscles, tendons, and bones differ in their developmental origins 2-8 , yet they interact during differentiation. Chen and Galloway 8 reported that artificial rupture of the myotome impedes syndetome formation. In contrast, cranial tendon progenitor cells emerge without dependence on muscles, yet muscle presence is essential for their normal differentiation 8. Huang et al 9. analyzed tendon development in forearms and fingers and found that tendons can be divided into a distal module showing cartilage-dependent development and a proximal module showing muscle-dependent development. In addition, the mechanical stress of muscle contraction affects the morphology of cartilage and bone during development 10. Previously, we found that mutual contact between muscles and the tendon-like structure immediately promotes the development of bones 11 and that there is a morphological association between muscles and bones 12. In summary, studies need to focus on the analysis of muscles, tendons, and bones as a single functional organ 13 rather than focusing on each as an independent tissue component. SRY-box containing gene 9 (Sox9) is a transcription factor essential for musculoskeletal system development. Sox9 is expressed in all cartilage progenitor cells and cartilage cells except hypertrophic chondrocytes 14,15 , and it plays a key role in a series of processes involved in endochondral...

Application of a Hyperelastic 3D Printed Scaffold for Mesenchymal Stem Cell-Based Fabrication of a Bizonal Tendon Enthesis-like Construct

“…Interestingly, recent embryonic development studies have reported that SOX9 is also essential for progenitor cells to differentiate into tenocytes (Sugimoto et al, 2012). In fact, consistent with our findings, Nagakura et al (Nagakura et al, 2020) showed that murine tenoprogenitor cells transiently express SOX9 in during development, and downregulate the same gene after differentiation to tenocytes in vivo.…”

Fetal development of the human trapezius and sternocleidomastoid muscles

“…The antero-inferior shift of the digastricus muscle due to formation of the intermediate tendon [ 11 ] seemed to drive separation of the SCM and trapezius muscles. Thus, bone formation at the muscle attachment can be affected by the mechanical load from the tendon [ 12 - 14 ]. However, the major driver underlying this separation seemed to be the developing clavicle.…”

Super-Enhancers and CTCF in Early Embryonic Cell Fate Decisions

“…PRS is linked to mutations in a Topologically Associated Domain (TAD, described below), containing a single protein coding gene, Sox9 ( Gordon et al, 2014 ). Sox9 plays a critical role during neural crest differentiation and craniofacial development ( Lee and Saint-Jeannet, 2011 ; Dash and Trainor, 2020 ; Nagakura et al, 2020 ) and enhancers near Sox9 have been implicated in craniofacial and chondrocyte development ( Liu and Lefebvre, 2015 ; Yao et al, 2015 ). PRS associated mutations are >1Mb from Sox9 and near a cluster of three enhancers the deletion of which leads to a 50% allele-specific decrease in Sox9 expression ( Long et al, 2020 ).…”