Abstract
SummaryProper functioning of the musculo-skeletal system requires the precise integration of bones, muscles and tendons. Complex morphogenetic events ensure that these elements are linked together in the appropriate 3D configuration. It has been difficult, however, to tease apart the mechanisms that regulate tissue morphogenesis. We find that deletion of Tbx5 in forelimb (or Tbx4 in hindlimbs) specifically affects muscle and tendon patterning without disrupting skeletal development thus suggesting that distinct cues regulate these processes. We identify muscle connective tissue as the site of action of these transcription factors and show that N-Cadherin and β-Catenin are key downstream effectors acting in muscle connective tissue regulating soft-tissue morphogenesis. In humans, TBX5 mutations lead to Holt-Oram syndrome, which is characterised by forelimb musculo-skeletal defects. Our results suggest that a focus on connective tissue is required to understand the aetiology of diseases affecting soft tissue formation.
Highlights
Dissecting the cues involved in patterning specific tissues in the developing embryo has proven to be a challenge
To analyse the muscle splitting and insertion phenotypes in more detail we carried out a 3D analysis of muscle morphology using Optical Projection Tomography (OPT) (DeLaurier et al, 2006; Sharpe et al, 2002) and High Resolution Episcopic Microscopy (HREM) (Weninger and Mohun, 2002)
As an example of abnormal muscle splitting and insertion in the mutant, we focused on the three triceps muscles of the forelimb, Triceps brachii longus (Tbl), M. triceps brachii medialis (Tbm) and Triceps brachii lateralis (Tblt), that insert on the olecranon process of the ulna (Fig. 1C)
Summary
Dissecting the cues involved in patterning specific tissues in the developing embryo has proven to be a challenge. The vertebrate limb has been a useful model to study these processes and much effort has been aimed at identifying the cues that pattern the limb skeleton (Mariani and Martin, 2003). For the limb skeleton to function properly it is critical that the appropriate associated muscles become anchored to the skeletal scaffold via the correct tendons. These three tissues must interact with each other in 3-dimensional space
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