title: A distinct regulatory region of the Bmp5 locus activates gene expression following adult bone fracture or soft tissue injury.
abstract: Bone morphogenetic proteins (BMPs) are key signaling molecules required for normal development of bones and other tissues. Previous studies have shown that null mutations in the mouse Bmp5 gene alter the size, shape and number of multiple bone and cartilage structures during development. Bmp5 mutations also delay healing of rib fractures in adult mutants, suggesting that the same signals used to pattern embryonic bone and cartilage are also reused during skeletal regeneration and repair. Despite intense interest in BMPs as agents for stimulating bone formation in clinical applications, little is known about the regulatory elements that control developmental or injury-induced BMP expression. To compare the DNA sequences that activate gene expression during embryonic bone formation and following acute injuries in adult animals, we assayed regions surrounding the Bmp5 gene for their ability to stimulate lacZ reporter gene expression in transgenic mice. Multiple genomic fragments, distributed across the Bmp5 locus, collectively coordinate expression in discrete anatomic domains during normal development, including in embryonic ribs. In contrast, a distinct regulatory region activated expression following rib fracture in adult animals. The same injury control region triggered gene expression in mesenchymal cells following tibia fracture, in migrating keratinocytes following dorsal skin wounding, and in regenerating epithelial cells following lung injury. The Bmp5 gene thus contains an "injury response" control region that is distinct from embryonic enhancers, and that is activated by multiple types of injury in adult animals.
authors.affiliation: Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA, USA; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Guenther
authors.affiliation: Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA, USA; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Emma
authors.initials: E
authors.lastname: Li
authors.affiliation: Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Misha C
authors.initials: MC
authors.lastname: Tran
authors.affiliation: Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA, USA; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Catriona Y
authors.initials: CY
authors.lastname: Logan
authors.affiliation: Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA, USA; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Roel
authors.initials: R
authors.lastname: Nusse
authors.affiliation: Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Luiz
authors.initials: L
authors.lastname: Pantalena-Filho
authors.affiliation: Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA; Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA. Electronic address: gpyang@stanford.edu.
authors.forename: George P
authors.initials: GP
authors.lastname: Yang
authors.affiliation: Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA, USA; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, USA. Electronic address: kingsley@stanford.edu.
authors.forename: David M
authors.initials: DM
authors.lastname: Kingsley
mesh_terms: D000818:Animals; D055417:Bone Morphogenetic Protein 5 / Q000235:genetics*; D050723:Fractures, Bone / Q000235:genetics*; D015870:Gene Expression / Q000235:genetics*; D006801:Humans; D008297:Male; D008822:Mice, Transgenic; D012045:Regulatory Sequences, Nucleic Acid; D017695:Soft Tissue Injuries / Q000235:genetics*
chemical_list: C525815:Bmp5 protein, mouse; D055417:Bone Morphogenetic Protein 5
keywords: Bmp5; Bone fracture; Developmental enhancer; Gene regulation; Injury response