Cdc42 is required for chondrogenesis and interdigital programmed cell death during limb development
Cdc42 is required for chondrogenesis and interdigital programmed cell death during limb development
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DOI：
10.1016/j.mod.2012.02.002
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发表时间：
2012-03-01
影响因子：
2.6
通讯作者：
Kamijo, Ryutaro
中科院分区：
文献类型：
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作者：
Aizawa, Ryo;Yamada, Atsushi;Kamijo, Ryutaro
Cdc42是小gtpase Rho亚家族的一员，被认为是多种细胞功能的调节剂，包括细胞骨架组织、细胞迁移、增殖和凋亡。然而，其组织特异性作用，特别是在哺乳动物肢体发育中的作用仍不清楚。为了研究Cdc42在肢体发育过程中的生理功能，我们制备了肢体芽间充质特异性灭活Cdc42(Cdc42(fl/fl)；Prx1-Cre)老鼠。Cdc42 (fl / fl);Prx1-Cre小鼠表现为四肢和身体短小，头盖骨异常钙化，腭裂，剑突断裂和并趾。长骨生长板软骨也存在严重缺陷，其特征是软骨细胞柱状组织丧失，肥大软骨细胞增厚和大量积聚，导致软骨内骨形成延迟，骨生长减少。原位杂交分析显示，Col10和Mmp13在非吸收性增生性软骨中的表达减少，表明Cdc42的缺失抑制了它们的终末分化。并趾Cdc42(fl/fl)；Prx1-Cre小鼠是由掌骨融合和指间程序性细胞死亡（ID-PCD）失败引起的。肢体芽全座原位杂交分析显示，Sox9的表达模式异位，而促进指间质凋亡的Bmp2、Msx1和Msx2的表达模式下调。这些结果表明，在肢体发育过程中，Cdc42对软骨形成和ID-PCD至关重要。2012爱思唯尔爱尔兰有限公司版权所有。
Cdc42, a member of the Rho subfamily of small GTPases, is known to be a regulator of multiple cellular functions, including cytoskeletal organization, cell migration, proliferation, and apoptosis. However, its tissue-specific roles, especially in mammalian limb development, remain unclear. To investigate the physiological function of Cdc42 during limb development, we generated limb bud mesenchyme-specific inactivated Cdc42 (Cdc42(fl/fl); Prx1-Cre) mice. Cdc42(fl/fl); Prx1-Cre mice demonstrated short limbs and body, abnormal calcification of the cranium, cleft palate, disruption of the xiphoid process, and syndactyly. Severe defects were also found in long bone growth plate cartilage, characterized by loss of columnar organization of chondrocytes, and thickening and massive accumulation of hypertrophic chondrocytes, resulting in delayed endochondral bone formation associated with reduced bone growth. In situ hybridization analysis revealed that expressions of Col10 and Mmp13 were reduced in non-resorbed hypertrophic cartilage, indicating that deletion of Cdc42 inhibited their terminal differentiation. Syndactyly in Cdc42(fl/fl); Prx1-Cre mice was caused by fusion of metacarpals and a failure of interdigital programmed cell death (ID-PCD). Whole mount in situ hybridization analysis of limb buds showed that the expression patterns of Sox9 were ectopic, while those of Bmp2, Msx1, and Msx2, known to promote apoptosis in the interdigital mesenchyme, were down-regulated. These results demonstrate that Cdc42 is essential for chondrogenesis and ID-PCD during limb development. (C) 2012 Elsevier Ireland Ltd. All rights reserved.