title: Gtf2ird1-Dependent Mohawk Expression Regulates Mechanosensing Properties of the Tendon.
abstract: Mechanoforces experienced by an organ are translated into biological information for cellular sensing and response. In mammals, the tendon connective tissue experiences and resists physical forces, with tendon-specific mesenchymal cells called tenocytes orchestrating extracellular matrix (ECM) turnover. We show that Mohawk (Mkx), a tendon-specific transcription factor, is essential in mechanoresponsive tenogenesis through regulation of its downstream ECM genes such as type I collagens and proteoglycans such as fibromodulin both in vivo and in vitro Wild-type (WT) mice demonstrated an increase in collagen fiber diameter and density in response to physical treadmill exercise, whereas in Mkx(-/-) mice, tendons failed to respond to the same mechanical stimulation. Furthermore, functional screening of the Mkx promoter region identified several upstream transcription factors that regulate Mkx In particular, general transcription factor II-I repeat domain-containing protein 1 (Gtf2ird1) that is expressed in the cytoplasm of unstressed tenocytes translocated into the nucleus upon mechanical stretching to activate the Mkx promoter through chromatin regulation. Here, we demonstrate that Gtf2ird1 is essential for Mkx transcription, while also linking mechanical forces to Mkx-mediated tendon homeostasis and regeneration.
authors.affiliation: Department of Systems BioMedicine, Tokyo Medical and Dental University, Tokyo, Japan Department of Orthopaedic Surgery, The Jikei University School of Medicine, Tokyo, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kayama
authors.affiliation: Department of Systems BioMedicine, Tokyo Medical and Dental University, Tokyo, Japan Department of Systems BioMedicine, National Institute of Child Health and Development, Tokyo, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Mori
authors.affiliation: Department of Systems BioMedicine, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Ito
authors.affiliation: Department of Systems BioMedicine, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Takahide
authors.initials: T
authors.lastname: Matsushima
authors.affiliation: Department of Systems BioMedicine, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Nakamichi
authors.affiliation: Department of Systems BioMedicine, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Hidetsugu
authors.initials: H
authors.lastname: Suzuki
authors.affiliation: Research Center for Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Shizuko
authors.initials: S
authors.lastname: Ichinose
authors.affiliation: Department of Orthopaedic Surgery, The Jikei University School of Medicine, Tokyo, Japan.
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Saito
authors.affiliation: Department of Orthopaedic Surgery, The Jikei University School of Medicine, Tokyo, Japan.
authors.forename: Keishi
authors.initials: K
authors.lastname: Marumo
authors.affiliation: Department of Systems BioMedicine, Tokyo Medical and Dental University, Tokyo, Japan Department of Systems BioMedicine, National Institute of Child Health and Development, Tokyo, Japan Department of Molecular and Experimental Medicine, The Scripps Research Institute, San Diego, California, USA asahara@scripps.edu.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Asahara
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D017353:Gene Deletion; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D008810:Mice, Inbred C57BL; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010805:Physical Conditioning, Animal; D011401:Promoter Regions, Genetic; D051381:Rats; D017208:Rats, Wistar; D013710:Tendons / Q000166:cytology / Q000502:physiology*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D015854:Up-Regulation; D016474:Weight-Bearing
chemical_list: C486558:Gtf2ird1 protein, mouse; D018398:Homeodomain Proteins; D009124:Muscle Proteins; D009687:Nuclear Proteins; D015534:Trans-Activators; C510657:mohawk protein, mouse