Bent bone dysplasia syndrome reveals nucleolar activity for FGFR2 in ribosomal DNA transcription
Bent bone dysplasia syndrome reveals nucleolar activity for FGFR2 in ribosomal DNA transcription
复制标题
DOI：
10.1093/hmg/ddu282
复制
发表时间：
2014-11-01
影响因子：
3.5
通讯作者：
Merrill, Amy E.
中科院分区：
文献类型：
--
作者：
Neben, Cynthia L.;Idoni, Brian;Merrill, Amy E.
成纤维细胞生长因子受体2（FGFR 2）在骨发育过程中促进骨祖细胞增殖和分化，但该受体如何激发这些不同的细胞反应仍不清楚。对FGFR 2-骨骼疾病弯曲骨发育不良综合征（BBDS）的分析表明，FGFR 2除了其在质膜上的典型信号传导活性之外，还从核仁内调节骨形成。以前，我们发现导致BBDS的独特FGFR 2突变降低了质膜上的受体水平，并降低了对细胞外FGF 2的反应性。在这项研究中，我们发现，这些突变，尽管减少典型的信号，增强核仁的FGFR 2在核糖体DNA（rDNA）启动子的占用。核仁FGFR 2通过与FGF 2和UBF 1的相互作用通过去抑制RUNX 2来激活rDNA转录。BBDS中FGFR 2核仁活性的增加提高了发育中骨中核糖体RNA的水平，从而促进骨祖细胞增殖并降低分化。将FGFR 2鉴定为骨中rDNA的转录调节因子出乎意料地揭示了FGF信号传导的核仁途径，其允许独立调节骨祖细胞增殖和分化。
Fibroblast growth factor receptor 2 (FGFR2) promotes osteoprogenitor proliferation and differentiation during bone development, yet how the receptor elicits these distinct cellular responses remains unclear. Analysis of the FGFR2-skeletal disorder bent bone dysplasia syndrome (BBDS) demonstrates that FGFR2, in addition to its canonical signaling activities at the plasma membrane, regulates bone formation from within the nucleolus. Previously, we showed that the unique FGFR2 mutations that cause BBDS reduce receptor levels at the plasma membrane and diminish responsiveness to extracellular FGF2. In this study, we find that these mutations, despite reducing canonical signaling, enhance nucleolar occupancy of FGFR2 at the ribosomal DNA (rDNA) promoter. Nucleolar FGFR2 activates rDNA transcription via interactions with FGF2 and UBF1 by derepressing RUNX2. An increase in the nucleolar activity of FGFR2 in BBDS elevates levels of ribosomal RNA in the developing bone, consequently promoting osteoprogenitor cell proliferation and decreasing differentiation. Identifying FGFR2 as a transcriptional regulator of rDNA in bone unexpectedly reveals a nucleolar route for FGF signaling that allows for independent regulation of osteoprogenitor cell proliferation and differentiation.