Shaping Skeletal Growth by Modular Regulatory Elements in the Bmp5 Gene

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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 genes provide a genomic mechanism for controlling precise growth domains in particular cartilages and bones, making it possible to separately regulate skeletal anatomy at highly specific locations in the body. Every bone in the skeleton has a specific shape and size. These characteristic features must be under separate genetic control, because individual bones can undergo striking morphological changes in different species. Researchers have long postulated that the morphology of individual bones arises from the local activity of many separate growth domains around each bone's surface. Differential growth within such domains could modify size, curvature, and formation of specific processes. Here, we show that local growth domains around individual bones are controlled by independent regulatory sequences in bone morphogenetic protein (BMP) genes. We identify multiple regulatory sequences in the Bmp5 gene that control expression in particular bones, rather than all bones. We show that some of these elements are remarkably specific for individual subdomains around the surface of individual bones. Finally, we show that local BMP signaling is necessary and sufficient to trigger highly localized growth patterns in ribs and nasal cartilages. These results suggest that the detailed pattern of growth of individual skeletal structures is encoded in part by multiple regulatory sequences in BMP genes. Gain and loss of anatomy-specific sequences in BMP genes may provide a flexible genomic mechanism for modifying local skeletal anatomy during vertebrate evolution.