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Notch gain of function inhibits chondrocyte differentiation via Rbpj-dependent suppression of Sox9.
J Bone Miner Res. 2013 Mar; 28(3):649-59.JB

Abstract

Notch signaling plays a critical role during development by directing the binary cell fate decision between progenitors and differentiated cells. Previous studies have shown sustained Notch activation in cartilage leads to chondrodysplasia. Genetic evidence indicates that Notch regulates limb bud mesenchymal stem cell differentiation into chondrocytes via an Rbpj-dependent Notch pathway. However, it is still unknown how Notch governs chondrogenesis in the axial skeleton where Notch serves a primary patterning function. We hypothesized that both Rbpj-dependent and Rbpj-independent Notch signaling mechanisms might be involved. Cartilage-specific Notch gain-of-function (GOF) mutant mice display chondrodysplasia accompanied by loss of Sox9 expression in vertebrae. To evaluate the contribution of an Rbpj-dependent Notch signaling to this phenotype, we deleted Rbpj on the Notch GOF background. These mice showed persistent spine abnormalities characterized by "butterfly" vertebrae suggesting that removal of Rbpj does not fully rescue the axial skeleton deformities caused by Notch GOF. However, Sox9 protein level was restored in Rbpj-deficient Notch GOF mice compared with Notch GOF mutants, demonstrating that regulation of Sox9 expression is canonical or Rbpj-dependent. To further understand the molecular basis of this regulation, we performed chromatin immunoprecipitation (ChIP) assays and detected the recruitment of the Rbpj/NICD transcription complex to Rbpj-binding sites upstream of the Sox9 promoter. The association of the Rbpj/NICD complex with the Sox9 promoter is associated with transcriptional repression of Sox9 in a cellular model of chondrocyte differentiation. Hence, Notch negatively regulates chondrocyte differentiation in the axial skeleton by suppressing Sox9 transcription, and Rbpj-independent Notch signaling mechanisms may also contribute to axial skeletogenesis.

Authors+Show Affiliations

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22991339

Citation

Chen, Shan, et al. "Notch Gain of Function Inhibits Chondrocyte Differentiation Via Rbpj-dependent Suppression of Sox9." Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research, vol. 28, no. 3, 2013, pp. 649-59.
Chen S, Tao J, Bae Y, et al. Notch gain of function inhibits chondrocyte differentiation via Rbpj-dependent suppression of Sox9. J Bone Miner Res. 2013;28(3):649-59.
Chen, S., Tao, J., Bae, Y., Jiang, M. M., Bertin, T., Chen, Y., Yang, T., & Lee, B. (2013). Notch gain of function inhibits chondrocyte differentiation via Rbpj-dependent suppression of Sox9. Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research, 28(3), 649-59. https://doi.org/10.1002/jbmr.1770
Chen S, et al. Notch Gain of Function Inhibits Chondrocyte Differentiation Via Rbpj-dependent Suppression of Sox9. J Bone Miner Res. 2013;28(3):649-59. PubMed PMID: 22991339.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Notch gain of function inhibits chondrocyte differentiation via Rbpj-dependent suppression of Sox9. AU - Chen,Shan, AU - Tao,Jianning, AU - Bae,Yangjin, AU - Jiang,Ming-Ming, AU - Bertin,Terry, AU - Chen,Yuqing, AU - Yang,Tao, AU - Lee,Brendan, PY - 2012/02/06/received PY - 2012/08/21/revised PY - 2012/09/04/accepted PY - 2012/9/20/entrez PY - 2012/9/20/pubmed PY - 2013/8/30/medline SP - 649 EP - 59 JF - Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research JO - J. Bone Miner. Res. VL - 28 IS - 3 N2 - Notch signaling plays a critical role during development by directing the binary cell fate decision between progenitors and differentiated cells. Previous studies have shown sustained Notch activation in cartilage leads to chondrodysplasia. Genetic evidence indicates that Notch regulates limb bud mesenchymal stem cell differentiation into chondrocytes via an Rbpj-dependent Notch pathway. However, it is still unknown how Notch governs chondrogenesis in the axial skeleton where Notch serves a primary patterning function. We hypothesized that both Rbpj-dependent and Rbpj-independent Notch signaling mechanisms might be involved. Cartilage-specific Notch gain-of-function (GOF) mutant mice display chondrodysplasia accompanied by loss of Sox9 expression in vertebrae. To evaluate the contribution of an Rbpj-dependent Notch signaling to this phenotype, we deleted Rbpj on the Notch GOF background. These mice showed persistent spine abnormalities characterized by "butterfly" vertebrae suggesting that removal of Rbpj does not fully rescue the axial skeleton deformities caused by Notch GOF. However, Sox9 protein level was restored in Rbpj-deficient Notch GOF mice compared with Notch GOF mutants, demonstrating that regulation of Sox9 expression is canonical or Rbpj-dependent. To further understand the molecular basis of this regulation, we performed chromatin immunoprecipitation (ChIP) assays and detected the recruitment of the Rbpj/NICD transcription complex to Rbpj-binding sites upstream of the Sox9 promoter. The association of the Rbpj/NICD complex with the Sox9 promoter is associated with transcriptional repression of Sox9 in a cellular model of chondrocyte differentiation. Hence, Notch negatively regulates chondrocyte differentiation in the axial skeleton by suppressing Sox9 transcription, and Rbpj-independent Notch signaling mechanisms may also contribute to axial skeletogenesis. SN - 1523-4681 UR - https://www.unboundmedicine.com/medline/citation/22991339/Notch_gain_of_function_inhibits_chondrocyte_differentiation_via_Rbpj_dependent_suppression_of_Sox9_ L2 - https://doi.org/10.1002/jbmr.1770 DB - PRIME DP - Unbound Medicine ER -