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Anatomy-Specific Enhancers of BMP Genes Fine-Tune Size and Shape of Individual Bones« Back to Volume 25, Issue 1, June 2009 - Table of Contents As the skeleton grows, constituent cartilage and bone tissues are formed into a remarkable range of sizes and shapes. Although the blueprints that sculpt individual bones must be encoded in the genome, little is known about how this occurs. A group headed by David Kingsley at Stanford has recently provided novel insight into how the anatomy of individual bones is regulated. Their story begins with the generally accepted concept that bone shapes are determined by differential growth and erosion along the surfaces of bones. For instance, preferential deposition and erosion on opposite surfaces of a bone would generate lateral displacement or curvature of the bone such as a rib. Localized regions of deposition and erosion would shape ridges, foramina, and other surface structures. The group focused their attention on the BMP5 gene because it is surrounded by large genomic regions containing regulatory elements required for normal developmental regulation and on rib development because BMP5 is expressed in the perichondrium surrounding ribs and ribs are suitable for detecting differential growth and erosion. The approach was to generate transgenic mouse embryos harboring both a lacZ reporter gene and genomic DNA corresponding to different regions of the BMP5 locus including surrounding genomic DNA. ß-galactosidase staining of late-stage transgenic embryos revealed specifically where the regulatory regions, ie, presumed enhancers, were active. The details of the experiments are beyond the scope of this abstract. However, a regulatory element within the coding region of the gene was found to drive expression of BMP5 in the perichondrium adjacent to the lateral aspect of the ribs, whereas regulatory sequences 100 kb 3’ to the coding region drove expression in the perichondrium of the medial aspect of the ribs. A number of confirmatory experiments was done, all of which suggested that BMP5 expression in different domains of the rib perichondrium is controlled by distinct regulatory elements in or near the BMP5 locus. In other words, anatomy-specific enhancers in BMP genes may provide a genomic mechanism for independent developmental control of local growth of individual bones. Discrete enhancers control growth in distinct anatomical domains of developing bones. Multiple anatomy-specific enhancers (filled circles) are spread across the Bmp5 locus. In ribs, two enhancers (green and purple circles) may respond to lineage domains established in somites to control growth on opposing sides of the ribs. Local growth on the lateral edge of rib surfaces promotes rib curvature and expansion of the thoracic cavity. Nasal cartilages form from cranial neural crest. Two enhancers (blue and orange circles) in the Bmp5 gene are expressed in different highly restricted locations, leading to characteristic branching patterns of the nasal turbinates. Reprinted with permission Guenther C, et al. PLoS Genetics. 2008;4:1-13. Copyright © PLoS 2008. All rights reserved. During these studies, the investigators also discovered 2 regulatory elements that controlled expression of BMP5 in nasal cartilage. These elements were distinct from those controlling BMP expression in ribs but like them mapped to locations within and 3’ from the coding region of the gene as shown in the Figure. The authors suggested that the proposed mechanism may not be limited to regulation of BMP5 but common to other developmentally regulated genes that are involved in fine-tuning morphogenesis. Editor’s CommentThis investigation provides novel insight into the fine-tuning of skeletal development. It is interesting to speculate how subtle radiographic findings that allow experts to distinguish between similar bone dysplasias might reflect disturbances in these regulatory mechanisms. William A. Horton, MD
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Volume 25 Number 1
June 2009
www.GGHjournal.com
ISSN 1932-9032
