title: MAML1 enhances the transcriptional activity of Runx2 and plays a role in bone development.
abstract: Mastermind-like 1 (MAML1) is a transcriptional co-activator in the Notch signaling pathway. Recently, however, several reports revealed novel and unique roles for MAML1 that are independent of the Notch signaling pathway. We found that MAML1 enhances the transcriptional activity of runt-related transcription factor 2 (Runx2), a transcription factor essential for osteoblastic differentiation and chondrocyte proliferation and maturation. MAML1 significantly enhanced the Runx2-mediated transcription of the p6OSE2-Luc reporter, in which luciferase expression was controlled by six copies of the osteoblast specific element 2 (OSE2) from the Runx2-regulated osteocalcin gene promoter. Interestingly, a deletion mutant of MAML1 lacking the N-terminal Notch-binding domain also enhanced Runx2-mediated transcription. Moreover, inhibition of Notch signaling did not affect the action of MAML1 on Runx2, suggesting that the activation of Runx2 by MAML1 may be caused in a Notch-independent manner. Overexpression of MAML1 transiently enhanced the Runx2-mediated expression of alkaline phosphatase, an early marker of osteoblast differentiation, in the murine pluripotent mesenchymal cell line C3H10T1/2. MAML1(-/-) embryos at embryonic day 16.5 (E16.5) had shorter bone lengths than wild-type embryos. The area of primary spongiosa of the femoral diaphysis was narrowed. At E14.5, extended zone of collagen type II alpha 1 (Col2a1) and Sox9 expression, markers of chondrocyte differentiation, and decreased zone of collagen type X alpha 1 (Col10a1) expression, a marker of hypertrophic chondrocyte, were observed. These observations suggest that chondrocyte maturation was impaired in MAML1(-/-) mice. MAML1 enhances the transcriptional activity of Runx2 and plays a role in bone development.
authors: Department of Systems BioMedicine, National Research Institute for Child Health and Development, Tokyo, Japan.
authors: Takashi
authors: T
authors: Watanabe
authors: Toshinao
authors: T
authors: Oyama
authors: Maki
authors: M
authors: Asada
authors: Daisuke
authors: D
authors: Harada
authors: Yoshiaki
authors: Y
authors: Ito
authors: Masayo
authors: M
authors: Inagawa
authors: Yutaka
authors: Y
authors: Suzuki
authors: Sumio
authors: S
authors: Sugano
authors: Ken-ichi
authors: K
authors: Katsube
authors: Gerard
authors: G
authors: Karsenty
authors: Toshihisa
authors: T
authors: Komori
authors: Motoo
authors: M
authors: Kitagawa
authors: Hiroshi
authors: H
authors: Asahara
mesh_terms: D000818:Animals; D001846:Bone Development / Q000235:genetics*; D002454:Cell Differentiation; D049109:Cell Proliferation; D019902:Chondrocytes / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D024043:Collagen Type II / Q000378:metabolism; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics / Q000378:metabolism; D047108:Embryonic Development / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D015675:Osteocalcin / Q000235:genetics / Q000378:metabolism; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism; D055758:SOX9 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: C447413:Col2a1 protein, mouse; D024043:Collagen Type II; D050659:Core Binding Factor Alpha 1 Subunit; C486455:Maml1 protein, mouse; D009687:Nuclear Proteins; D051880:Receptors, Notch; C493716:Runx2 protein, mouse; D055758:SOX9 Transcription Factor; C527933:Sox9 protein, mouse; D014157:Transcription Factors; D015675:Osteocalcin