Analysis of the molecular cascade responsible for mesodermal limb chondrogenesis: Sox genes and BMP signaling.
Here, we have studied how Sox genes and BMP signaling are functionally coupled during limb chondrogenesis. Using the experimental model of TGFbeta1-induced interdigital digits, we dissect the sequence of morphological and molecular events during in vivo chondrogenesis. Our results show that Sox8 and Sox9 are the most precocious markers of limb cartilage, and their induction is independent and precedes the activation of BMP signaling. Sox10 appears also to cooperate with Sox9 and Sox8 in the establishment of the digit cartilages. In addition, we show that experimental induction of Sox gene expression in the interdigital mesoderm is accompanied by loss of the apoptotic response to exogenous BMPs. L-Sox5 and Sox6 are respectively induced coincident and after the expression of Bmpr1b in the prechondrogenic aggregate, and their activation correlates with the induction of Type II Collagen and Aggrecan genes in the differentiating cartilages. The expression of Bmpr1b precedes the appearance of morphological changes in the prechondrogenic aggregate and establishes a landmark from which the maintenance of the expression of all Sox genes and the progress of cartilage differentiation becomes dependent on BMPs. Moreover, we show that Ventroptin precedes Noggin in the modulation of BMP activity in the developing cartilages. In summary, our findings suggest that Sox8, Sox9, and Sox10 have a cooperative function conferring chondrogenic competence to limb mesoderm in response to BMP signals. In turn, BMPs in concert with Sox9, Sox6, and L-Sox5 would be responsible for the execution and maintenance of the cartilage differentiation program.
Departamento de Biología Celular y Fisiología, Instituto de Investigaciones Biomédicas, UNAM, México DF 04510, México.
J
J
Chimal-Monroy
J
J
Rodriguez-Leon
J A
JA
Montero
Y
Y
Gañan
D
D
Macias
R
R
Merino
J M
JM
Hurle
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D052005:Bone Morphogenetic Protein Receptors, Type I; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins; D002356:Cartilage / Q000196:embryology / Q000502:physiology; D002642:Chick Embryo; D020219:Chondrogenesis / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005121:Extremities / Q000196:embryology*; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D055428:Growth Differentiation Factor 5; D006609:High Mobility Group Proteins / Q000235:genetics / Q000378:metabolism; D008648:Mesoderm / Q000187:drug effects / Q000378:metabolism*; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D017978:Receptors, Growth Factor / Q000235:genetics / Q000378:metabolism; D055758:SOX9 Transcription Factor; D055755:SOXD Transcription Factors; D055757:SOXE Transcription Factors; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D053773:Transforming Growth Factor beta1; D000099176:Noggin Protein
D052005:Bone Morphogenetic Protein Receptors, Type I; D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D005136:Eye Proteins; D055428:Growth Differentiation Factor 5; D006609:High Mobility Group Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D011506:Proteins; D017978:Receptors, Growth Factor; D055758:SOX9 Transcription Factor; D055755:SOXD Transcription Factors; D055757:SOXE Transcription Factors; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D000099176:Noggin Protein; C486602:CHRDL1 protein, human; C490301:SOX5 protein, human; C486270:SOX6 protein, human; C508960:TGFB1 protein, human