Runx1 and Runx2 cooperate during sternal morphogenesis
Runx1 and Runx2 cooperate during sternal morphogenesis
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DOI：
10.1242/dev.045005
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发表时间：
2010-04-01
期刊：
影响因子：
4.6
通讯作者：
Takeda, Shu
中科院分区：
文献类型：
--
作者：
Kimura, Ayako;Inose, Hiroyuki;Takeda, Shu
软骨细胞分化受到各种转录因子的严格调控，包括Runx 2和Runx 3;然而，Runx 1在软骨细胞分化中的生理作用仍然未知。为了研究Runx 1的作用，我们产生了间充质细胞特异性和软骨细胞特异性Runx 1缺陷小鼠[分别为Prx 1 Runx 1（f/f）小鼠和alpha 1（II）Runx 1（f/f）小鼠]，以规避Runx 1缺陷小鼠的胚胎致死性。然后，我们将这些小鼠与Runx 2突变小鼠交配，以获得间充质细胞特异性或软骨细胞特异性Runx 1; Runx 2双突变小鼠[分别为Prx 1 DKO小鼠和α 1（II）DKO小鼠]。Prx 1 Runx 1（f/f）小鼠显示胸骨发育延迟，而Prx 1 DKO小鼠完全缺乏胸骨。相比之下，α 1（II）Runx 1（f/f）小鼠和α 1（II）DKO小鼠未显示任何异常胸骨形态发生或软骨细胞分化。值得注意的是，Runx 1、Runx 2和Prx 1-Cre转基因在胸骨中特异性共表达，这解释了异常仅限于胸骨的观察结果。在组织学上，间充质细胞在Prx 1 DKO小鼠的预期胸骨中正常凝聚;然而，在间充质凝聚之后，对软骨细胞谱系的承诺显著受损。原位杂交分析表明，α 1（II）胶原蛋白（Col 2a 1-小鼠基因组信息学），Sox 5和Sox 6的表达在Prx 1 DKO小鼠的前瞻性胸骨严重减弱，而Sox 9的表达是不变的。分子分析显示Runx 1和Runx 2诱导Sox 5和Sox 6的表达，这导致通过直接调节启动子活性诱导α 1（II）胶原蛋白表达。总的来说，这些结果表明，Runx 1和Runx 2协同调节胸骨形态发生和间充质细胞的承诺，成为软骨细胞通过Sox 5和Sox 6的诱导。
Chondrocyte differentiation is strictly regulated by various transcription factors, including Runx2 and Runx3; however, the physiological role of Runx1 in chondrocyte differentiation remains unknown. To examine the role of Runx1, we generated mesenchymal-cell-specific and chondrocyte-specific Runx1-deficient mice [Prx1 Runx1(f/f) mice and alpha 1(II) Runx1(f/f) mice, respectively] to circumvent the embryonic lethality of Runx1-deficient mice. We then mated these mice with Runx2 mutant mice to obtain mesenchymal-cell-specific or chondrocyte-specific Runx1; Runx2 double-mutant mice [Prx1 DKO mice and alpha 1(II) DKO mice, respectively]. Prx1 Runx1(f/f) mice displayed a delay in sternal development and Prx1 DKO mice completely lacked a sternum. By contrast, alpha 1(II) Runx1(f/f) mice and alpha 1(II) DKO mice did not show any abnormal sternal morphogenesis or chondrocyte differentiation. Notably, Runx1, Runx2 and the Prx1-Cre transgene were co-expressed specifically in the sternum, which explains the observation that the abnormalities were limited to the sternum. Histologically, mesenchymal cells condensed normally in the prospective sternum of Prx1 DKO mice; however, commitment to the chondrocyte lineage, which follows mesenchymal condensation, was significantly impaired. In situ hybridization analyses demonstrated that the expression of alpha 1(II) collagen (Col2a1-Mouse Genome Informatics), Sox5 and Sox6 in the prospective sternum of Prx1 DKO mice was severely attenuated, whereas Sox9 expression was unchanged. Molecular analyses revealed that Runx1 and Runx2 induce the expression of Sox5 and Sox6, which leads to the induction of alpha 1(II) collagen expression via the direct regulation of promoter activity. Collectively, these results show that Runx1 and Runx2 cooperatively regulate sternal morphogenesis and the commitment of mesenchymal cells to become chondrocytes through the induction of Sox5 and Sox6.