title: Early onset of Runx2 expression caused craniosynostosis, ectopic bone formation, and limb defects.
abstract: RUNX2 is an essential transcription factor for osteoblast differentiation, because osteoblast differentiation is completely blocked in Runx2-deficient mice. However, it remains to be clarified whether RUNX2 is sufficient for osteoblast differentiation during embryogenesis. To address this issue, Runx2 transgenic mice were generated under the control of the Prrx1 promoter, which directs the transgene expression to mesenchymal cells before the onset of bone development. The transgene expression was detected in the cranium, limb buds, and the region from the mandible to anterior chest wall. The skull became small and the limbs were shortened depending on the levels of the transgene expression. Early onset of Runx2 expression in the cranial mesenchyme induced mineralization on E13.0, when no mineralization was observed in wild-type mice, and resulted in craniosynostosis as shown by the closure of sutures and fontanelles on E18.5. Col1a1 and Spp1 expressions were detected in the mineralized regions on E12.5-13.5. The limb bones were hypoplastic and fused, and ectopic bones were formed in the hands and feet. Col2a1 expression was inhibited but Col1a1 expression was induced in the limb buds on E12.5. In the anterior chest wall, ectopic bones were formed through the process of intramembranous ossification, interrupting the formation of cartilaginous anlagen of sternal manubrium. These findings indicate that RUNX2 is sufficient to direct mesenchymal cells to osteoblasts and lead to intramembranous bone formation during embryogenesis; Runx2 inhibits chondrocyte differentiation at an early stage; and that Runx2 expression at appropriate level, times and spaces during embryogenesis is essential for skeletal development.
authors.affiliation: Department of Cell Biology, Unit of Basic Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8588, Japan.
authors.forename: Takafumi
authors.initials: T
authors.lastname: Maeno
authors.forename: Takeshi
authors.initials: T
authors.lastname: Moriishi
authors.forename: Carolina Andrea
authors.initials: CA
authors.lastname: Yoshida
authors.forename: Hisato
authors.initials: H
authors.lastname: Komori
authors.forename: Naoko
authors.initials: N
authors.lastname: Kanatani
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Izumi
authors.forename: Kunio
authors.initials: K
authors.lastname: Takaoka
authors.forename: Toshihisa
authors.initials: T
authors.lastname: Komori
mesh_terms: D000818:Animals; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D002356:Cartilage / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation; D019902:Chondrocytes / Q000378:metabolism / Q000473:pathology; D002828:Choristoma / Q000150:complications* / Q000000981:diagnostic imaging / Q000196:embryology* / Q000473:pathology; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism*; D003398:Craniosynostoses / Q000150:complications* / Q000000981:diagnostic imaging / Q000196:embryology* / Q000473:pathology; D005145:Face; D005453:Fluorescence; D049452:Green Fluorescent Proteins / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism; D018878:Limb Buds / Q000002:abnormalities* / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D010006:Osteoblasts / Q000378:metabolism / Q000473:pathology; D010012:Osteogenesis; D012886:Skull / Q000000981:diagnostic imaging / Q000196:embryology / Q000473:pathology; D055114:X-Ray Microtomography
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; D018398:Homeodomain Proteins; C489936:Prrx1 protein, mouse; C493716:Runx2 protein, mouse; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins