TY - JOUR
T1 - Sox9 is required for cartilage formation
AU - Bi, Weimin
AU - Deng, Jian Min
AU - Zhang, Zhaoping
AU - Behringer, Richard R.
AU - De Crombrugghe, Benoit
N1 - Funding Information:
We thank A. Bradley for AB-1 ES and SNL 76/7 STO cell lines; M. Wakamiya for IRES-lacZ-pA loxP-flanked PGKneobpA plasmid; E. Vuorio and L. Bridgewater for RNA in situ hybridization probes; D. Whitworth for assistance with embryos; H. Eberspaecher for advice on histology; G. Pinero for histological assistance; and A. Bradley, R. Johnson and V. Lefebvre for helpful comments on the manuscript. The anti-collagen II monoclonal antibody developed by T. Linsenmayer was obtained from the Developmental Studies Hybridoma Bank. This study was supported by NIH grants HD30284 to R.R.B. and AR42919 to R.R.B. and B. de C.
PY - 1999/5
Y1 - 1999/5
N2 - Chondrogenesis results in the formation of cartilages, initial skeletal elements that can serve as templates for endochondral bone formation. Cartilage formation begins with the condensation of mesenchyme cells followed by their differentiation into chondrocytes. Although much is known about the terminal differentiation products that are expressed by chondrocytes, little is known about the factors that specify the chondrocyte lineage. SOX9 is a high-mobility-group (HMG) domain transcription factor that is expressed in chondrocytes and other tissues. In humans, SOX9 haploinsufficiency results in campomelic dysplasia, a lethal skeletal malformation syndrome, and XY sex reversal. During embryogenesis, Sox9 is expressed in all cartilage primordia and cartilages, coincident with the expression of the collagen α1(II) gene (Col2a1; refs 8,11,12). Sox9 is also expressed in other tissues, including the central nervous and urogenital systems. Sox9 binds to essential sequences in the Col2a1 and collagen α2(XI) gene (Col11a2) chondrocyte-specific enhancers and can activate these enhancers in non-chondrocytic cells. Here, Sox9 is identified as a regulator of the chondrocyte lineage. In mouse chimaeras, Sox9(-/-) cells are excluded from all cartilages but are present as a juxtaposed mesenchyme that does not express the chondrocyte-specific markers Col2a1, Col9a2, Col11a2 and Agc. This exclusion occurred cell autonomously at the condensing mesenchyme stage of chondrogenesis. Moreover, no cartilage developed in teratomas derived from Sox9(-/-) embryonic stem (ES) cells. Our results identify Sox9 as the first transcription factor that is essential for chondrocyte differentiation and cartilage formation.
AB - Chondrogenesis results in the formation of cartilages, initial skeletal elements that can serve as templates for endochondral bone formation. Cartilage formation begins with the condensation of mesenchyme cells followed by their differentiation into chondrocytes. Although much is known about the terminal differentiation products that are expressed by chondrocytes, little is known about the factors that specify the chondrocyte lineage. SOX9 is a high-mobility-group (HMG) domain transcription factor that is expressed in chondrocytes and other tissues. In humans, SOX9 haploinsufficiency results in campomelic dysplasia, a lethal skeletal malformation syndrome, and XY sex reversal. During embryogenesis, Sox9 is expressed in all cartilage primordia and cartilages, coincident with the expression of the collagen α1(II) gene (Col2a1; refs 8,11,12). Sox9 is also expressed in other tissues, including the central nervous and urogenital systems. Sox9 binds to essential sequences in the Col2a1 and collagen α2(XI) gene (Col11a2) chondrocyte-specific enhancers and can activate these enhancers in non-chondrocytic cells. Here, Sox9 is identified as a regulator of the chondrocyte lineage. In mouse chimaeras, Sox9(-/-) cells are excluded from all cartilages but are present as a juxtaposed mesenchyme that does not express the chondrocyte-specific markers Col2a1, Col9a2, Col11a2 and Agc. This exclusion occurred cell autonomously at the condensing mesenchyme stage of chondrogenesis. Moreover, no cartilage developed in teratomas derived from Sox9(-/-) embryonic stem (ES) cells. Our results identify Sox9 as the first transcription factor that is essential for chondrocyte differentiation and cartilage formation.
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U2 - 10.1038/8792
DO - 10.1038/8792
M3 - Article
C2 - 10319868
AN - SCOPUS:0345711458
SN - 1061-4036
VL - 22
SP - 85
EP - 89
JO - Nature Genetics
JF - Nature Genetics
IS - 1
ER -