Shaping skeletal growth by modular regulatory elements in the Bmp5 gene.
Shaping skeletal growth by modular regulatory elements in the Bmp5 gene.
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通过 Bmp5 基因中的模块化调控元件塑造骨骼生长。
DOI：
10.1371/journal.pgen.1000308
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发表时间：
2008-12
期刊：
影响因子：
4.5
通讯作者：
Kingsley DM
中科院分区：
文献类型：
--
作者：
Guenther C;Pantalena-Filho L;Kingsley DM
软骨和骨骼形成了各种不同的形状和尺寸，这些形状和尺寸是脊椎动物对不同生活方式的许多解剖适应的基础。尽管个体软骨和骨结构的形态蓝图必须以某种方式编码在基因组中，但我们目前对指导特定骨骼精确生长模式的详细基因组机制知之甚少。我们进行了大规模的增强子调查，以确定控制小鼠 Bmp5 基因发育表达的调控结构，该基因编码特定骨骼特征正常形态所需的分泌信号分子。尽管 Bmp5 在许多骨骼前体中表达，但不同的增强子控制各个骨骼中的表达。值得注意的是，我们在这里表明，沿着个体骨骼结构（包括肋骨和鼻软骨）表面的高度受限的空间子域也存在不同的增强子。转基因、无效和调节突变证实，这些解剖学特异性序列足以引发骨骼形态的局部变化，并且是在单独的骨表面上建立正常生长速率所必需的。我们的研究结果表明，单个骨骼是复合结构，其详细的生长模式是由许多较小的谱系和基因表达域构建的。 BMP 基因中的各个增强子提供了一种基因组机制，用于控制特定软骨和骨骼的精确生长域，从而可以单独调节体内高度特定位置的骨骼解剖结构。骨骼中的每块骨头都有特定的形状和大小。这些特征必须受到单独的遗传控制，因为不同物种的个体骨骼可能会发生显着的形态变化。研究人员长期以来一直假设，单个骨骼的形态是由每个骨骼表面周围许多独立生长域的局部活动产生的。这些域内的差异生长可以改变特定过程的尺寸、曲率和形成。在这里，我们证明了个体骨骼周围的局部生长域是由骨形态发生蛋白（BMP）基因中的独立调控序列控制的。我们确定了 Bmp5 基因中的多个调控序列，这些序列控制特定骨骼（而不是所有骨骼）的表达。我们表明，其中一些元素对于单个骨骼表面周围的单个子域具有显着的特异性。最后，我们证明局部 BMP 信号传导对于触发肋骨和鼻软骨的高度局部生长模式是必要且充分的。这些结果表明，个体骨骼结构生长的详细模式部分是由 BMP 基因中的多个调控序列编码的。 BMP 基因中解剖学特异性序列的获得和丢失可能提供灵活的基因组机制，用于在脊椎动物进化过程中修改局部骨骼解剖结构。
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.
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