title: Gli1 protein participates in Hedgehog-mediated specification of osteoblast lineage during endochondral ossification.
abstract: With regard to Hedgehog signaling in mammalian development, the majority of research has focused on Gli2 and Gli3 rather than Gli1. This is because Gli1(-/-) mice do not show any gross abnormalities in adulthood, and no detailed analyses of fetal Gli1(-/-) mice are available. In this study, we investigated the physiological role of Gli1 in osteogenesis. Histological analyses revealed that bone formation was impaired in Gli1(-/-) fetuses compared with WT fetuses. Gli1(-/-) perichondrial cells expressed neither runt-related transcription factor 2 (Runx2) nor osterix, master regulators of osteogenesis, in contrast to WT cells. In vitro analyses showed that overexpression of Gli1 up-regulated early osteogenesis-related genes in both WT and Runx2(-/-) perichondrial cells, and Gli1 activated transcription of those genes via its association with their 5'-regulatory regions, underlying the function of Gli1 in the perichondrium. Moreover, Gli1(-/-);Gli2(-/-) mice showed more severe phenotypes of impaired bone formation than either Gli1(-/-) or Gli2(-/-) mice, and osteoblast differentiation was impaired in Gli1(-/-);Gli3(-/-) perichondrial cells compared with Gli3(-/-) cells in vitro. These data suggest that Gli1 itself can induce early osteoblast differentiation, at least to some extent, in a Runx2-independent manner. It also plays a redundant role with Gli2 and is involved in the repressor function of Gli3 in osteogenesis. On the basis of these findings, we propose that upon Hedgehog input, Gli1 functions collectively with Gli2 and Gli3 in osteogenesis.
authors.affiliation: Center for Disease Biology and Integrative Medicine, The University of Tokyo, Tokyo 113-0033; Department of Sensory and Motor System Medicine, The University of Tokyo, Tokyo 113-0033. Electronic address: hojo@bmw.t.u-tokyo.ac.jp.
authors.forename: Hironori
authors.initials: H
authors.lastname: Hojo
authors.affiliation: Center for Disease Biology and Integrative Medicine, The University of Tokyo, Tokyo 113-0033. Electronic address: soba@bmw.t.u-tokyo.ac.jp.
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Ohba
authors.affiliation: Center for Disease Biology and Integrative Medicine, The University of Tokyo, Tokyo 113-0033; Department of Sensory and Motor System Medicine, The University of Tokyo, Tokyo 113-0033.
authors.forename: Fumiko
authors.initials: F
authors.lastname: Yano
authors.affiliation: Department of Sensory and Motor System Medicine, The University of Tokyo, Tokyo 113-0033.
authors.forename: Taku
authors.initials: T
authors.lastname: Saito
authors.affiliation: Department of Sensory and Motor System Medicine, The University of Tokyo, Tokyo 113-0033.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Ikeda
authors.affiliation: Center for Disease Biology and Integrative Medicine, The University of Tokyo, Tokyo 113-0033; Department of Sensory and Motor System Medicine, The University of Tokyo, Tokyo 113-0033.
authors.forename: Keiji
authors.initials: K
authors.lastname: Nakajima
authors.affiliation: Center for Disease Biology and Integrative Medicine, The University of Tokyo, Tokyo 113-0033; Department of Sensory and Motor System Medicine, The University of Tokyo, Tokyo 113-0033.
authors.forename: Yuske
authors.initials: Y
authors.lastname: Komiyama
authors.affiliation: Center for Animal Resources and Development (CARD), Kumamoto University, Kumamoto 860-0811, Japan.
authors.forename: Naomi
authors.initials: N
authors.lastname: Nakagata
authors.affiliation: Center for Animal Resources and Development (CARD), Kumamoto University, Kumamoto 860-0811, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Suzuki
authors.affiliation: Department of Sensory and Motor System Medicine, The University of Tokyo, Tokyo 113-0033.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Takato
authors.affiliation: Department of Sensory and Motor System Medicine, The University of Tokyo, Tokyo 113-0033.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kawaguchi
authors.affiliation: Center for Disease Biology and Integrative Medicine, The University of Tokyo, Tokyo 113-0033.
authors.forename: Ung-Il
authors.initials: UI
authors.lastname: Chung
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002460:Cell Line; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics / Q000378:metabolism; D005333:Fetus / Q000166:cytology / Q000196:embryology*; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*; D010012:Osteogenesis; D013131:Spine / Q000166:cytology / Q000196:embryology*; D015854:Up-Regulation / Q000502:physiology; D000071676:Zinc Finger Protein GLI1; D000075746:Zinc Finger Protein Gli2; D000074290:Zinc Finger Protein Gli3
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; C498520:Gli1 protein, mouse; C000618551:Gli2 protein, mouse; C465571:Gli3 protein, mouse; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; C493716:Runx2 protein, mouse; D000071676:Zinc Finger Protein GLI1; D000075746:Zinc Finger Protein Gli2; D000074290:Zinc Finger Protein Gli3