Runx2-I isoform contributes to fetal bone formation even in the absence of specific N-terminal amino acids.
Runx2-I isoform contributes to fetal bone formation even in the absence of specific N-terminal amino acids.
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DOI：
10.1371/journal.pone.0108294
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Kiyono H
中科院分区：
文献类型：
--
作者：
Okura H;Sato S;Kishikawa S;Kaneto S;Nakashima T;Yoshida N;Takayanagi H;Kiyono H
Runt相关转录因子2（Runx 2）基因编码转录因子Runx 2，它是成骨细胞发育的主要调节因子;这种蛋白质的不足会导致骨发育障碍，如锁骨颅骨发育不良。Runx 2有两种亚型，Runx 2-II和Runx 2-I，每种亚型的产生分别由一个独特的启动子控制：远端启动子（P1）和近端启动子（P2）。虽然有几项研究集中在两种Runx 2亚型之间的差异和相似之处，但它们在骨形成中的作用尚未最终确定，部分原因是Runx 2-I靶向小鼠模型不可用。在这项研究中，我们建立了一种新的Runx 2操纵的小鼠模型，其中Runx 2-I的第一个ATG被TGA（终止密码子）取代，并在Runx 2-I的第一个内含子插入新霉素抗性基因（neo）盒。纯合子Runx 2-Ineo/neo小鼠显示Runx 2-I表达严重降低，而Runx 2-II表达基本保留。Runx 2-Ineo/neo小鼠表现出新生儿致死性，在这些小鼠中，膜内骨化比软骨内骨化更严重缺陷，可能是因为与Runx 2-II相比，Runx 2-I参与膜内骨化的程度更高。有趣的是，neo的缺失挽救了上述表型，表明Runx 2-I的同种型特异性N-末端区域在功能上对骨发育不是必需的。总之，我们的研究结果提供了一个新的线索，导致更好地了解Runx 2亚型在成骨细胞发育中的作用。
The Runt-related transcription factor 2 (Runx2) gene encodes the transcription factor Runx2, which is the master regulator of osteoblast development; insufficiency of this protein causes disorders of bone development such as cleidocranial dysplasia. Runx2 has two isoforms, Runx2-II and Runx2-I, and production of each isoform is controlled by a unique promoter: a distal promoter (P1) and a proximal promoter (P2), respectively. Although several studies have focused on differences and similarities between the two Runx2 isoforms, their individual roles in bone formation have not yet been determined conclusively, partly because a Runx2-I-targeted mouse model is not available. In this study, we established a novel Runx2-manipulated mouse model in which the first ATG of Runx2-I was replaced with TGA (a stop codon), and a neomycin-resistant gene (neo) cassette was inserted at the first intron of Runx2-I. Homozygous Runx2-Ineo/neo mice showed severely reduced expression of Runx2-I, whereas Runx2-II expression was largely retained. Runx2-Ineo/neo mice showed neonatal lethality, and in these mice, intramembranous ossification was more severely defective than endochondral ossification, presumably because of the greater involvement of Runx2-I, compared with that of Runx2-II in intramembranous ossification. Interestingly, the depletion of neo rescued the above-described phenotypes, indicating that the isoform-specific N-terminal region of Runx2-I is not functionally essential for bone development. Taken together, our results provide a novel clue leading to a better understanding of the roles of Runx2 isoforms in osteoblast development.
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DOI：
10.1083/jcb.153.1.87
发表时间：
2001-04-02
期刊：
The Journal of cell biology
影响因子：
--
作者：
Ueta C;Iwamoto M;Kanatani N;Yoshida C;Liu Y;Enomoto-Iwamoto M;Ohmori T;Enomoto H;Nakata K;Takada K;Kurisu K;Komori T
通讯作者：
Komori T
DOI：
10.2741/3977
发表时间：
2012-01-01
期刊：
Frontiers in bioscience (Landmark edition)
影响因子：
--
作者：
Lam K;Zhang DE
通讯作者：
Zhang DE
影响因子：
64.8
作者：
Ono, Masahiro;Yaguchi, Hiroko;Sakaguchi, Shimon
通讯作者：
Sakaguchi, Shimon
影响因子：
64.5
作者：
Mundlos, S;Otto, F;Olsen, BR
通讯作者：
Olsen, BR
DOI：
10.1073/pnas.151236498
发表时间：
2001-07-17
影响因子：
11.1
作者：
Choi, JY;Pratap, J;Stein, GS
通讯作者：
Stein, GS