Nature Genetics
22, 85 - 89 (1999)
doi:10.1038/8792
Sox9 is required for cartilage formationWeimin Bi, Jian Min Deng, Zhaoping Zhang, Richard R. Behringer
& Benoit de Crombrugghe
Department of Molecular Genetics, The University of Texas, M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
Correspondence should be addressed to Benoit de Crombrugghe benoit_decrombrugghe@molgen.mdacc.tmc.edu or Richard R. Behringer bhr@molgen.mdacc.tmc.eduChondrogenesis 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 chondrocytes1,
2,
3,
little is known about the factors that specify the chondrocyte lineage4,
5,
6. SOX9 is a high-mobility-group (HMG) domain transcription
factor that is expressed in chondrocytes and other tissues7,
8,
9,
10,
11,
12.
In humans, SOX9 haploinsufficiency results in campomelic dysplasia,
a lethal skeletal malformation syndrome, and XY sex reversal7,
13,
14,
15,
16.
During embryogenesis, Sox9 is expressed in all cartilage primordia
and cartilages, coincident with the expression of the collagen  1(II)
gene (Col2a1; refs 8,11, 12). Sox9 is also
expressed in other tissues, including the central nervous and urogenital systems8,
9,
10,
11,
12. Sox9 binds to essential sequences in the Col2a1
and collagen 2(XI) gene (Col11a2) chondrocyte-specific
enhancers and can activate these enhancers in non-chondrocytic cells17,
18,
19. 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.
|
