Tbx4 and tbx5 acting in connective tissue are required for limb muscle and tendon patterning.
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 Tbx5 in forelimbs (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 beta-Catenin are key downstream effectors acting in muscle connective tissue and regulating soft-tissue morphogenesis. In humans, TBX5 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.
Division of Developmental Biology, MRC-National Institute for Medical Research, Mill Hill, London NW7 1AA, United Kingdom.
Peleg
P
Hasson
April
A
DeLaurier
Michael
M
Bennett
Elena
E
Grigorieva
L A
LA
Naiche
Virginia E
VE
Papaioannou
Timothy J
TJ
Mohun
Malcolm P O
MP
Logan
D000818:Animals; D019521:Body Patterning / Q000502:physiology; D015820:Cadherins / Q000378:metabolism; D003238:Connective Tissue / Q000196:embryology* / Q000378:metabolism; D005121:Extremities / Q000196:embryology*; D005552:Forelimb / Q000196:embryology; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D006614:Hindlimb / Q000196:embryology; D018878:Limb Buds / Q000196:embryology; D051379:Mice; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000196:embryology*; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism*; D013710:Tendons / Q000196:embryology*; D051176:beta Catenin / Q000378:metabolism
C495267:CTNNB1 protein, mouse; D015820:Cadherins; C489083:Cdh2 protein, mouse; D020825:T-Box Domain Proteins; C103172:T-box transcription factor 5; C103177:Tbx4 protein, mouse; D051176:beta Catenin