title: Foxp1/2/4 regulate endochondral ossification as a suppresser complex.
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.
authors.affiliation: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: Haixia
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: Wenrong
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: Zhengju
authors.initials: Z
authors.lastname: Yao
authors.affiliation: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Wan
authors.affiliation: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Cao
authors.affiliation: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: Lingling
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: Jianzhi
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: Hanjun
authors.initials: H
authors.lastname: Li
authors.affiliation: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: Rujiang
authors.initials: R
authors.lastname: Zhou
authors.affiliation: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: Baojie
authors.initials: B
authors.lastname: Li
authors.affiliation: Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences (CAS), Shanghai 200032, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Wei
authors.affiliation: Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated the Sixth People׳s Hospital, Shanghai, China.
authors.forename: Zhenlin
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Champalimaud Neuroscience Programme, Champalimaud Centre for the Unknown, Lisbon, Portugal.
authors.forename: Catherine A
authors.initials: CA
authors.lastname: French
authors.affiliation: Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, TX 78712, USA.
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Dekker
authors.affiliation: Developmental Genetics Section, National Human Genome Research Institute, NIH, MD 20892, USA.
authors.forename: Yingzi
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, The Netherlands.
authors.forename: Simon E
authors.initials: SE
authors.lastname: Fisher
authors.affiliation: Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, TX 78712, USA.
authors.forename: Haley O
authors.initials: HO
authors.lastname: Tucker
authors.affiliation: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200240, China. Electronic address: xzguo2005@sjtu.edu.cn.
authors.forename: Xizhi
authors.initials: X
authors.lastname: Guo
mesh_terms: D000818:Animals; D001842:Bone and Bones / Q000378:metabolism; D019556:COS Cells; D002113:Calcification, Physiologic; D002522:Chlorocebus aethiops; D019902:Chondrocytes / Q000378:metabolism* / Q000473:pathology; D020219:Chondrogenesis / Q000235:genetics; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism; D005121:Extremities / Q000196:embryology; D051858:Forkhead Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D057809:HEK293 Cells; D006801:Humans; D006984:Hypertrophy; D019426:Integrases / Q000378:metabolism; D008822:Mice, Transgenic; D010012:Osteogenesis; D011485:Protein Binding; D012097:Repressor Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; D051858:Forkhead Transcription Factors; C432917:Foxp1 protein, mouse; C432918:Foxp2 protein, mouse; C472854:Foxp4 protein, mouse; D012097:Repressor Proteins; C045073:Cre recombinase; D019426:Integrases
keywords: Endochondral ossification; Foxp1; Foxp2; Foxp4; Osteoblast; Transcriptional repressor