Sox5 and Sox6 are needed to develop and maintain source, columnar, and hypertrophic chondrocytes in the cartilage growth plate.
Sox5 and Sox6 encode Sry-related transcription factors that redundantly promote early chondroblast differentiation. Using mouse embryos with three or four null alleles of Sox5 and Sox6, we show that they are also essential and redundant in major steps of growth plate chondrocyte differentiation. Sox5 and Sox6 promote the development of a highly proliferating pool of chondroblasts between the epiphyses and metaphyses of future long bones. This pool is the likely cellular source of growth plates. Sox5 and Sox6 permit formation of growth plate columnar zones by keeping chondroblasts proliferating and by delaying chondrocyte prehypertrophy. They allow induction of chondrocyte hypertrophy and permit formation of prehypertrophic and hypertrophic zones by delaying chondrocyte terminal differentiation induced by ossification fronts. They act, at least in part, by down-regulating Ihh signaling, Fgfr3, and Runx2 and by up-regulating Bmp6. In conclusion, Sox5 and Sox6 are needed for the establishment of multilayered growth plates, and thereby for proper and timely development of endochondral bones.
Dept. of Biomedical Engineering, Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Ave., ND-20, Cleveland, OH 44195, USA.
Patrick
P
Smits
Peter
P
Dy
Srijeet
S
Mitra
Véronique
V
Lefebvre
D000818:Animals; D000831:Animals, Newborn; D001846:Bone Development / Q000502:physiology; D055418:Bone Morphogenetic Protein 6; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism; D001842:Bone and Bones / Q000002:abnormalities / Q000033:anatomy & histology / Q000196:embryology; D002356:Cartilage / Q000166:cytology / Q000196:embryology* / Q000473:pathology; D002454:Cell Differentiation / Q000502:physiology*; D002455:Cell Division / Q000502:physiology; D019902:Chondrocytes / Q000166:cytology / Q000378:metabolism*; D050659:Core Binding Factor Alpha 1 Subunit; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000033:anatomy & histology / Q000502:physiology*; D005260:Female; D005865:Gestational Age; D006132:Growth Plate / Q000166:cytology* / Q000473:pathology / Q000502:physiology; D053823:Hedgehog Proteins; D006609:High Mobility Group Proteins / Q000235:genetics / Q000378:metabolism*; D006984:Hypertrophy / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D044162:Parathyroid Hormone-Related Protein / Q000235:genetics / Q000378:metabolism; D000072079:Patched Receptors; D011247:Pregnancy; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D051498:Receptor, Fibroblast Growth Factor, Type 3; D011956:Receptors, Cell Surface; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics / Q000378:metabolism; D055755:SOXD Transcription Factors; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
C525817:Bmp6 protein, mouse; D055418:Bone Morphogenetic Protein 6; D019485:Bone Morphogenetic Proteins; D050659:Core Binding Factor Alpha 1 Subunit; D004268:DNA-Binding Proteins; D053823:Hedgehog Proteins; D006609:High Mobility Group Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D044162:Parathyroid Hormone-Related Protein; D000072079:Patched Receptors; D011506:Proteins; D011956:Receptors, Cell Surface; D017468:Receptors, Fibroblast Growth Factor; C490301:SOX5 protein, human; C486270:SOX6 protein, human; D055755:SOXD Transcription Factors; C089186:Sox5 protein, mouse; C095939:Sox6 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; C496366:Fgfr3 protein, mouse; D011505:Protein-Tyrosine Kinases; D051498:Receptor, Fibroblast Growth Factor, Type 3