Overlapping expression of Runx1(Cbfa2) and Runx2(Cbfa1) transcription factors supports cooperative induction of skeletal development
Overlapping expression of Runx1(Cbfa2) and Runx2(Cbfa1) transcription factors supports cooperative induction of skeletal development
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DOI：
10.1002/jcp.20210
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发表时间：
2005-04-01
影响因子：
5.6
通讯作者：
Drissi, MH
中科院分区：
文献类型：
--
作者：
Smith, N;Dong, YF;Drissi, MH
确定调节骨骼发育的遗传途径对于纠正各种软骨和骨骼异常是必要的。Runx家族转录因子在器官发育和细胞分化中起着重要作用。初步研究表明，Runx1和Runx2在E12.5时发育胚胎的软骨前间质中均有表达。去除Runx2基因完全抑制了骨的形成，但这些小鼠的软骨原素却完全形成。在本研究中，我们假设Runx1可能弥补体内Runx2的缺失，从而诱导骨骼形成和发育的早期阶段。使用Runx1(+/-)- lac - z小鼠的组织学P-gal染色切片显示Runx1启动子在软骨细胞前细胞群中具有活性。使用Runx1和Runx2特异性探针进行原位杂交表明，这两种因子在胚胎早期发育期间在间充质干细胞祖细胞中表达。在小鼠骨骼形成的后期阶段，Runx1不存在于肥大软骨中，而Runx2存在于这些成熟的软骨细胞群中。通过实时RT-PCR和Western blot分析对Runx表达的定量分析显示，Runx1和Runx2在胚胎发生过程中受到差异调节，这表明这些转录调节因子在骨骼形成过程中具有时间作用。我们提供的证据表明，单倍不足导致杂合子Runx2和Runx1突变小鼠模型出现正常的胚胎骨骼；然而，在颅骨中发现骨形成的延迟。总之，我们的研究结果支持Runx1和Runx2在骨骼发育过程中的功能，Runx1可能在介导软骨内和膜内骨形成的早期事件中发挥作用，而Runx2是软骨细胞和成骨细胞分化晚期的有效诱导剂。(C) 2004 Wiley-Liss, Inc。
identifying the genetic pathways that regulate skeletal development is necessary to correct a variety of cartilage and bone abnormalities. The Runx family of transcription factors play a fundamental role in organ development and cell differentiation. Initial studies have shown that both Runx1 and Runx2 are expressed in pre-chondrogenic mesenchyme of the developing embryo at E12.5. Abrogation of the Runx2 gene completely inhibits bone formation yet the cartilage anlagen in these mice is fully formed. In the present study, we hypothesized that Runx1 may compensate for the lack of Runx2 in vivo to induce the early stages of skeletal formation and development. Histologic P-gal stained sections using the Runx1(+/-)-Lac-Z mice demonstrate Runx1 promoter activity in pre-chondrocytic cell populations. In situ hybridization using Runx1 and Runx2 specific probes indicate that both factors are expressed in mesenchymal stem cell progenitors during early embryonic development. During later stages of mouse skeletal formation, Runx1 is excluded from the hypertrophic cartilage while Runx2 is present in these matured chondrocyte populations. Quantification of Runx expression by real time RT-PCR and Western blot analyses reveals that Runx1 and Runx2 are differentially modulated during embryogenesis suggesting a temporal role for each of these transcriptional regulators during skeletal formation. We provide evidence that haploinsufficiency results in normal appearing embryo skeletons of heterozygote Runx2 and Runx1 mutant Mouse models; however, a delay in bone formation was identified in the calvarium. In summary, our results support a function for Runx1 and Runx2 during skeletal development with a possible role for Runx1 in mediating early events of endochondral and intramembranous bone formation, while Runx2 is a potent inducer of late stages of chondrocyte and osteoblast differentiation. (C) 2004 Wiley-Liss, Inc.