The transcription factor Sox9 has essential roles in successive steps of the chondrocyte differentiation pathway and is required for expression of Sox5 and Sox6.

By H. Akiyama, Marie-Christine Chaboissier, James F. Martin, A. Schedl, B. De Crombrugghe. Genes & Development, 2002

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To examine whether the transcription factor Sox9 has an essential role during the sequential steps of chondrocyte differentiation, we have used the Cre/loxP recombination system to generate mouse embryos in which either Sox9 is missing from undifferentiated mesenchymal cells of limb buds or the Sox9 gene is inactivated after chondrogenic mesenchymal condensations. Inactivation of Sox9 in limb buds before mesenchymal condensations resulted in a complete absence of both cartilage and bone, but markers for the different axes of limb development showed a normal pattern of expression. Apoptotic domains within the developing limbs were expanded, suggesting that Sox9 suppresses apoptosis. Expression of Sox5 and Sox6, two other Sox genes involved in chondrogenesis, was no longer detected. Moreover, expression of Runx2, a transcription factor needed for osteoblast differentiation, was also abolished. Embryos, in which Sox9 was deleted after mesenchymal condensations, exhibited a severe generalized chondrodysplasia, similar to that in Sox5; Sox6 double-null mutant mice. Most cells were arrested as condensed mesenchymal cells and did not undergo overt differentiation into chondrocytes. Furthermore, chondrocyte proliferation was severely inhibited and joint formation was defective. Although Indian hedgehog, Patched1, parathyroid hormone-related peptide (Pthrp), and Pth/Pthrp receptor were expressed, their expression was down-regulated. Our experiments further suggested that Sox9 is also needed to prevent conversion of proliferating chondrocytes into hypertrophic chondrocytes. We conclude that Sox9 is required during sequential steps of the chondrocyte differentiation pathway.

Subfields: Cancer Research, Genetics, Immunology

View Paper: https://www.semanticscholar.org/paper/e65963187a4e29b254fc91c0e5fb771b639a3d8d

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Citations in the corpus

Histone deacetylase 4 controls chondrocyte hypertrophy during skeletogenesis. (2004, background): “…of ity by HDAC4, the activity of Sox9, a transcription factor Runx2 with the Runx2 promoter was readily detected required for commitment to the chondrocyte lineage by ChIP assay, and this interaction was diminished in (Akiyama et al., 2002), was only modestly repressed by the presence of HDAC4.”
The Sox9 transcription factor determines glial fate choice in the developing spinal cord. (2003, methodology): “Mice with a Sox9 allele (Akiyama et al. 2002) were kept as homozygotes, or as heterozygotes in the presence of the nestin Cre transgene (Tronche et al.”
SOX9 is an intestine crypt transcription factor, is regulated by the Wnt pathway, and represses the CDX2 and MUC2 genes (2004, background): “chondrogenesis (Hartmann and Tabin, 2000), a process in which SOX9 function is essential (Akiyama et al., 2002; Bi et al., 1999).”
Runx2 and Runx3 are essential for chondrocyte maturation, and Runx2 regulates limb growth through induction of Indian hedgehog. (2004, background): “Although Sox9, which is an inhibitor of chondrocyte maturation (Akiyama et al. 2002), was strongly expressed in E13.”
Interactions between Sox9 and β-catenin control chondrocyte differentiation (2004, background): “Overall, this phenotype presents striking similarities with that of Sox9; Col2a1–Cre in which Sox9 was inactivated in chondrocytes (Akiyama et al. 2002).”
Developmental regulation of the growth plate (2003, methodology): “When a Cre- loxP strategy (a powerful technology that allows target genes to be spliced out of specific cells and tissues) was used to knock Sox9 out selectively from early limb mesenchyme, no cartilage condensations formed and increased apoptosis in the mesenchyme was note”
Development of the endochondral skeleton. (2013, background): “In addition to its early role, SOX9 regulates subsequent chondrocyte differentiation in collaboration with SOX5 and SOX6 (Smits et al. 2001; Akiyama et al. 2002).”
Canonical Wnt/beta-catenin signaling prevents osteoblasts from differentiating into chondrocytes. (2005, background): “Earlier studies have implicated a role for canonical Wnt/ β-catenin signaling in chondrogenesis (Akiyama et al., 2002; Hartmann and Tabin, 2001; Ryu et al., 2002), and the characterization of the Lrp5 mutant mice suggested that canonical Wnt signaling is required for osteoblast function and/or proli”