shaping skeletal growth by modular regulatory elements in the bmp5 gene模块化的监管元素形成骨骼的生长的bmp5基因.pdfVIP

Shaping Skeletal Growth by Modular Regulatory Elements in the Bmp5 Gene Catherine Guenther1,2., Luiz Pantalena-Filho1,2., David M. Kingsley1,2* 1 Department of Developmental Biology, Stanford University School of Medicine, Stanford, California, United States of America, 2 Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California, United States of America Abstract Cartilage and bone are formed into a remarkable range of shapes and sizes that underlie many anatomical adaptations to different lifestyles in vertebrates. Although the morphological blueprints for individual cartilage and bony structures must somehow be encoded in the genome, we currently know little about the detailed genomic mechanisms that direct precise growth patterns for particular bones. We have carried out large-scale enhancer surveys to identify the regulatory architecture controlling developmental expression of the mouse Bmp5 gene, which encodes a secreted signaling molecule required for normal morphology of specific skeletal features. Although Bmp5 is expressed in many skeletal precursors, different enhancers control expression in individual bones. Remarkably, we show here that different enhancers also exist for highly restricted spatial subdomains along the surface of individual skeletal structures, including ribs and nasal cartilages. Transgenic, null, and regulatory mutations confirm that these anatomy-specific sequences are sufficient to trigger local changes in skeletal morphology and are required for establishing normal growth rates on separate bone surfaces. Our findings suggest that individual bones are composite structures whose detailed growth patterns are built from many smaller lineage and gene expression domains. Individual enhancers in BMP