Notch gain of function inhibits chondrocyte differentiation via Rbpj-dependent suppression of Sox9

Shan Chen, Jianning Tao, Yangjin Bae, Ming Ming Jiang, Terry Bertin, Yuqing Chen, Tao Yang, Brendan Lee

Research output: Contribution to journalArticlepeer-review

42 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)649-659
Number of pages11
JournalJournal of Bone and Mineral Research
Volume28
Issue number3
DOIs
StatePublished - Mar 2013
Externally publishedYes

Keywords

  • AXIAL SKELETON
  • CHONDROCYTE
  • CHONDRODYSPLASIA
  • GENETIC MOUSE MODEL
  • NOTCH SIGNALING
  • SOX9

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine

Fingerprint Dive into the research topics of 'Notch gain of function inhibits chondrocyte differentiation via Rbpj-dependent suppression of Sox9'. Together they form a unique fingerprint.

Cite this