Tbx4 and tbx5 acting in connective tissue are required for limb muscle and tendon patterning.

[holt-oram syndrome]

Proper functioning of the musculoskeletal system requires the precise integration of bones , muscles , and tendons . Complex morphogenetic events ensure that these elements are linked together in the appropriate three -dimensional configuration . It has been difficult , however , to tease apart the mechanisms that regulate tissue morphogenesis . We find that deletion of Tbx 5 in forelimbs (or Tbx 4 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 beta -Catenin are key downstream effectors acting in muscle connective tissue and regulating soft -tissue morphogenesis . In humans , TBX 5 mutations lead to Holt-Oram syndrome , which is characterized by forelimb musculoskeletal defects . Our results suggest that a focus on connective tissue is required to understand the etiology of diseases affecting soft tissue formation .