Molecular Medicine & Pathology seminar: Morphogenesis and matrix assembly at myotendinous junctions Event as iCalendar

12 March 2013

3:30 - 4:30pm

Venue: Seminar Room 501-505, Building 501, 85 Park Road, Grafton

Development of a functional musculoskeletal system requires that muscle cells attach at their ends through tendons. Muscle attachments rely on Integrin (Itg) and Dystrophin (Dys) -dependent adhesion and defects in human Itg/Dys ligands in the extracellular matrix (ECM) such as Laminin (Lam) are associated with muscular dystrophy. Lam, collagen and other ECM proteins form complex fibrillar networks at myotendinous junctions (MTJs) to bear the forces of muscle contractions, but how these structures are assembled and maintained remains unclear. Our recent work has revealed a complex series of interactions between myoblasts and tenocytes during MTJ morphogenesis in zebrafish. We have shown that the Itg ligand Thrombospondin-4 (Thbs4) is essential for ECM assembly and muscle attachment at MTJs. Myoblasts initially secrete their own Thbs4 to promote attachment, but downregulate it upon differentiation, at which point Thbs4b production becomes localized to tenocytes as MTJs mature. Depletion of Thbs4 causes muscles to detach upon contraction, and local secretion of Thbs4 in genetic mosaics can rescue these defects. Furthermore, Thbs4 is required to localize Lam and activate Itg signaling at MTJs. Thus, our results reveal a novel role for Thbs4 as a regulator of muscle attachment, and as a critical scaffold for assembly of other ECM components. Thbs proteins may initiate ECM assembly in other contexts where they are required, particularly those that involve high levels of Itg signaling, and understanding the functions of Thbs4 may provide novel strategies to treat muscular dystrophies. Our analyses of tendon morphogenesis in the embryo also reveals distinct mechanisms that pattern the attachments of different types of cranial and trunk muscles.

Anyone wanting to meet with Professor Schilling should email Professor Phil Crosier