Notch signaling controls chondrocyte hypertrophy via indirect regulation of Sox9

Anat Kohn, Timothy P. Rutkowski, Zhaoyang Liu, Anthony J. Mirando, Michael J. Zuscik, Regis J. O'Keefe, Matthew J. Hilton

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

Abstract

RBPjk-dependent Notch signaling regulates both the onset of chondrocyte hypertrophy and the progression to terminal chondrocyte maturation during endochondral ossification. It has been suggested that Notch signaling can regulate Sox9 transcription, although how this occurs at the molecular level in chondrocytes and whether this transcriptional regulation mediates Notch control of chondrocyte hypertrophy and cartilage development is unknown or controversial. Here we have provided conclusive genetic evidence linking RBPjk-dependent Notch signaling to the regulation of Sox9 expression and chondrocyte hypertrophy by examining tissue-specific Rbpjk mutant (Prx1Cre;Rbpjk f/f), Rbpjk mutant/Sox9 haploinsufficient (Prx1Cre;Rbpjk f/f;Sox9 f/+), and control embryos for alterations in SOX9 expression and chondrocyte hypertrophy during cartilage development. These studies demonstrate that Notch signaling regulates the onset of chondrocyte maturation in a SOX9-dependent manner, while Notch-mediated regulation of terminal chondrocyte maturation likely functions independently of SOX9. Furthermore, our in vitro molecular analyses of the Sox9 promoter and Notch-mediated regulation of Sox9 gene expression in chondrogenic cells identified the ability of Notch to induce Sox9 expression directly in the acute setting, but suppresses Sox9 transcription with prolonged Notch signaling that requires protein synthesis of secondary effectors.

Original languageEnglish
Article number15021
JournalBone Research
Volume3
DOIs
StatePublished - Aug 11 2015

Fingerprint

Dive into the research topics of 'Notch signaling controls chondrocyte hypertrophy via indirect regulation of Sox9'. Together they form a unique fingerprint.

Cite this