Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur, Kanpur 208016, Uttar Pradesh, India.
Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur, Kanpur 208016, Uttar Pradesh, India.
Dev Biol. 2014 May 15;389(2):192-207. doi: 10.1016/j.ydbio.2014.02.015. Epub 2014 Feb 27.
In vertebrates, BMP signaling has been demonstrated to be sufficient for bone formation in several tissue contexts. This suggests that genes necessary for bone formation are expressed in a BMP signaling dependent manner. However, till date no gene has been reported to be expressed in a BMP signaling dependent manner in bone. Our aim was to identify such genes. On searching the literature we found that several microarray experiments have been conducted where the transcriptome of osteogenic cells in absence and presence of BMP signaling activation have been compared. However, till date, there is no evidence to suggest that any of the genes found to be upregulated in presence of BMP signaling in these microarray analyses is indeed a target of BMP signaling in bone. We wanted to utilize this publicly available information to identify candidate BMP signaling target genes in vivo. We performed a meta-analysis of six such comparable microarray datasets. This analysis and subsequent experiments led to the identification of five targets of BMP signaling in bone that are conserved both in mouse and chick. Of these Lox, Klf10 and Gpr97 are likely to be direct transcriptional targets of BMP signaling pathway. Dpysl3, is a novel BMP signaling target identified in our study. Our data demonstrate that Dpysl3 is important for osteogenic differentiation of mesenchymal cells and is involved in cell secretion. We have demonstrated that the expression of Dpysl3 is co-operatively regulated by BMP signaling and Runx2. Based on our experimental data, in silico analysis of the putative promoter-enhancer regions of Bmp target genes and existing literature, we hypothesize that BMP signaling collaborates with multiple signaling pathways to regulate the expression of a unique set of genes involved in endochondral ossification.
在脊椎动物中，已有研究表明 BMP 信号足以在多种组织环境中促进骨形成。这表明，骨形成所需的基因是通过 BMP 信号依赖性方式表达的。然而，迄今为止，尚未有基因被报道在骨中以 BMP 信号依赖性方式表达。我们的目的是鉴定这样的基因。在文献搜索中，我们发现已经进行了几项微阵列实验，其中比较了成骨细胞在缺乏和存在 BMP 信号激活的情况下的转录组。然而，迄今为止，没有证据表明在这些微阵列分析中发现的在 BMP 信号存在的情况下上调的任何基因实际上是骨中 BMP 信号的靶标。我们希望利用这些公开可用的信息来鉴定体内候选 BMP 信号靶基因。我们对六个类似的微阵列数据集进行了荟萃分析。这项分析和随后的实验导致鉴定出了在骨中 BMP 信号的五个靶标，这些靶标在小鼠和鸡中都是保守的。其中，Lox、Klf10 和 Gpr97 可能是 BMP 信号通路的直接转录靶标。Dpysl3 是我们研究中发现的一个新的 BMP 信号靶标。我们的数据表明，Dpysl3 对于间充质细胞的成骨分化是重要的，并且参与细胞分泌。我们已经证明，Dpysl3 的表达是由 BMP 信号和 Runx2 协同调节的。基于我们的实验数据、对 Bmp 靶基因的假定启动子增强子区域的计算机分析以及现有文献，我们假设 BMP 信号与多种信号通路合作，以调节参与软骨内骨化的一组独特基因的表达。
