Shaping Skeletal Growth by Modular Regulatory Elements in the Bmp5 Gene

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.

Evolved tooth gain in sticklebacks is associated with acis-regulatory allele ofBmp6

“…BMP family members have been implicated in several vertebrate evolved traits: size and shape of the beak in Darwin's finches, size and shape of the jaw in cichlids, jaw and skull variation in brachycephalic dogs, and avian feather patterning (47)(48)(49)(50). Although based on a limited number of reported cases and possibly affected by ascertainment biases, this apparent reuse of the same signaling pathway across taxa may reflect a predisposition for Bmp genes to be used during morphological evolution, perhaps due to having complex, modular cis-regulatory architecture to generate evolutionary variation (51,52).…”

Muscle force regulates bone shaping for optimal load-bearing capacity during embryogenesis

“…The involvement of mechanical load in bone development has been the subject of a long-standing debate (Guenther et al, 2008;Hall, 1971;Murray and Selby, 1930;Nowlan et al, 2008;Klein-Nulend et al, 1986). To unravel the contribution of mechanical forces to bone morphogenesis, it is first necessary to determine the magnitude of the forces acting on developing bones, their source and the onset of this effect.…”

“…Bone modeling involves growth and resorption, which occur simultaneously on separate surfaces, and has been previously suggested as a mechanism for bone shaping (Enlow, 1962;Guenther et al, 2008). For example, accelerated radial bone growth on the convex side of the ribs and resorption on the concave side has been suggested to form their curvature (Epker and Frost, 1966).…”

“…However, in vitro studies of chick embryos in which bone segments were cultured using various experimental protocols found that, apart from varying delays in the mineralization process, the overall shape of the bone rudiments was unaffected (Bradley, 1970;Hamburger and Waugh, 1940;Murray and Selby, 1930). Moreover, a study of the regulation of rib curvature identified differential expression of Bmp5 around the surface of the ribs determined by anatomyspecific enhancers, supporting the autonomous nature of bone shaping (Guenther et al, 2008). Yet, it is unclear whether the mechanism that shapes the ribs is also responsible for shaping other bones.…”

Genomic Strategies for Terminal Cell Fate Specification

“…5.7(B) (Guenther et al, 2008). Bones are shaped by local growth patterns during their development, and this function is modulated by Bmp5.…”