Foxp1/2/4 regulate endochondral ossification as a suppresser complex

Haixia Zhao, Wenrong Zhou, Zhengju Yao, Yong Wan, Jingjing Cao, Lingling Zhang, Jianzhi Zhao, Hanjun Li, Rujiang Zhou, Baojie Li, Gang Wei, Zhenlin Zhang, Catherine A. French, Joseph D. Dekker, Yingzi Yang, Simon E. Fisher, Haley O. Tucker, Xizhi Guo

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

Abstract

Osteoblast induction and differentiation in developing long bones is dynamically controlled by the opposing action of transcriptional activators and repressors. In contrast to the long list of activators that have been discovered over past decades, the network of repressors is not well-defined. Here we identify the expression of Foxp1/2/4 proteins, comprised of Forkhead-box (Fox) transcription factors of the Foxp subfamily, in both perichondrial skeletal progenitors and proliferating chondrocytes during endochondral ossification. Mice carrying loss-of-function and gain-of-function Foxp mutations had gross defects in appendicular skeleton formation. At the cellular level, over-expression of Foxp1/2/4 in chondroctyes abrogated osteoblast formation and chondrocyte hypertrophy. Conversely, single or compound deficiency of Foxp1/2/4 in skeletal progenitors or chondrocytes resulted in premature osteoblast differentiation in the perichondrium, coupled with impaired proliferation, survival, and hypertrophy of chondrocytes in the growth plate. Foxp1/2/4 and Runx2 proteins interacted in vitro and in vivo, and Foxp1/2/4 repressed Runx2 transactivation function in heterologous cells. This study establishes Foxp1/2/4 proteins as coordinators of osteogenesis and chondrocyte hypertrophy in developing long bones and suggests that a novel transcriptional repressor network involving Foxp1/2/4 may regulate Runx2 during endochondral ossification.

Original languageEnglish (US)
Pages (from-to)242-254
Number of pages13
JournalDevelopmental Biology
Volume398
Issue number2
DOIs
StatePublished - Feb 15 2015
Externally publishedYes

Bibliographical note

Funding Information:
This work was supported by grants to Xizhi Guo (the 973 program of China 2014CB942902 and 2012CB966903 ; NSFC 31171396 , 31271553 , 81421061 and 31100624 ), to Dr. Simon E. Fisher ( UK Wellcome Trust , 080971 ) and to Dr. Haley Tucker ( NIH /USA, R01CA31534 ).

Publisher Copyright:
© 2014 Elsevier Inc.

Keywords

  • Endochondral ossification
  • Foxp1
  • Foxp2
  • Foxp4
  • Osteoblast
  • Transcriptional repressor

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