Shox2 is required for chondrocyte proliferation and maturation in proximal limb skeleton
Shox2 is required for chondrocyte proliferation and maturation in proximal limb skeleton
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DOI：
10.1016/j.ydbio.2007.03.518
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发表时间：
2007-06-15
影响因子：
2.7
通讯作者：
Chen, YiPing
中科院分区：
文献类型：
--
作者：
Yu, Ling;Liu, Hongbing;Chen, YiPing
矮个子同源框基因Shox的突变会导致与Turner、Leri-Weill软骨发育不良和Langer中脑发育不良综合征相关的生长迟缓，这标志着前臂和小腿的缩短。我们在这里报告，与人类的Shox突变相反，小鼠的Shox2缺陷导致发育中的四肢中的柱脚类实际上消失了，而斑足类和自体类看起来相对正常。这种表型与Shox2的表达限制在肢芽中的近端间充质细胞，然后限制在与形成花柱足相关的软骨细胞上是一致的。在Shox2(-/-)胚胎中，花柱足间充质凝聚正常启动，但软骨成分随后无法生长、软骨形成和软骨内成骨。Runx2和Runx3的显著下调可能是软骨细胞缺乏肥大的原因，而IHH表达的下调可能是突变的茎足类软骨细胞增殖显著减少的原因。我们进一步证明，在Shox2胚胎的近侧肢体中，Bmp4的异位表达增强可能是Runx2下调的基础，因为异位应用外源BMP4抑制了Runx2在早期肢芽中的表达。此外，我们发现，小鼠Shox2与人类Shox类似，可以在基因表达上扮演相反的角色：在不同的细胞类型中作为转录激活因子或抑制因子。我们的结果证实了Shox2通过Runx2和Runx3控制软骨细胞的成熟，从而在调控花柱脚类动物的生长中发挥了关键作用。(C)2007 Elsevier Inc.保留所有权利。
Mutations in the short stature homeobox gene SHOX lead to growth retardation associated with Turner, Leri-Weill dyschondrosteosis, and Langer mesomelic dysplasia syndromes, which marked the shortening of the forearms and lower legs. We report here that in contrast to the SHOX mutations in humans, Shox2 deficiency in mice leads to a virtual elimination of the stylopod in the developing limbs, while the zeugopod and autopod appear relatively normal. This phenotype is consistent with the restriction of the Shox2 expression to the proximal mesenchyme in the limb bud and later to chondrocytes associated with the forming stylopod. In the Shox2(-/-) embryo, the mesenchymal condensation for the stylopod initiates normally but the cartilaginous element subsequently fails in growth, chondrogenesis and endochondral ossification. A dramatic down-regulation of Runx2 and Runx3 could account for the lack of chondrocyte hypertrophy, while a down-regulation of Ihh expression may be responsible for a significant reduction in chondrocyte proliferation in the mutant stylopod. We further demonstrate that an enhanced and ectopic Bmp4 expression in the proximal limb of the Shox2 embryo may underlie the down-regulation of Runx2, as ectopically applied exogenous BMP4 represses Runx2 expression in the early limb bud. Moreover, we show that mouse Shox2, similar to human SHOX, can perforin opposite roles on gene expression: either as a transcription activator or a repressor in different cell types. Our results establish a key role for Shox2 in regulating the growth of stylopod by controlling chondrocyte maturation via Runx2 and Runx3. (C) 2007 Elsevier Inc. All rights reserved.