Lack of Cul4b, an E3 Ubiquitin Ligase Component, Leads to Embryonic Lethality and Abnormal Placental Development
Lack of Cul4b, an E3 Ubiquitin Ligase Component, Leads to Embryonic Lethality and Abnormal Placental Development
复制标题
缺乏 Cul4b（E3 泛素连接酶成分）会导致胚胎致死和胎盘发育异常
DOI：
10.1371/journal.pone.0037070
复制
发表时间：
2012-05-14
期刊：
影响因子：
3.7
通讯作者：
Gong, Yaoqin
中科院分区：
文献类型：
--
作者：
Jiang, Baichun;Zhao, Wei;Gong, Yaoqin
Cullin-RING连接酶（CRL）复合物参与多种细胞过程的调节，包括细胞周期进程、转录、信号转导和发育。作为支架蛋白，cullin对于连接酶复合物的组装至关重要，连接酶复合物识别并靶向蛋白体降解的各种底物。CUL 4 B基因突变是X连锁精神发育迟滞的主要原因之一。我们在这里报告Cul 4 b基因敲除小鼠，其中外显子3至5被删除的生成和表征。与具有CUL 4 B无效突变的人类半合子男性存活至成年相反，CUL 4 b无效小鼠胚胎显示严重的发育停滞，并且通常在胚胎第9.5天（E9.5）之前死亡。在Cul 4 b无效胚胎中观察到细胞周期蛋白E（CRL（CUL 4 B）底物）的积累。Cul 4 b杂合子回收率降低，表现出严重的发育迟缓。Cul 4 b杂合子的胎盘结构紊乱，血管化受损，这可能是导致发育迟缓的原因。在人CUL 4 B杂合子中，Cul 4 b无效细胞被选择用于Cul 4 b杂合子，导致不同组织中不同程度的偏斜X-失活。总之，我们的研究结果表明，CUL 4 B是小鼠胚胎发育不可或缺的。
Cullin-RING ligases (CRLs) complexes participate in the regulation of diverse cellular processes, including cell cycle progression, transcription, signal transduction and development. Serving as the scaffold protein, cullins are crucial for the assembly of ligase complexes, which recognize and target various substrates for proteosomal degradation. Mutations in human CUL4B, one of the eight members in cullin family, are one of the major causes of X-linked mental retardation. We here report the generation and characterization of Cul4b knockout mice, in which exons 3 to 5 were deleted. In contrast to the survival to adulthood of human hemizygous males with CUL4B null mutation, Cul4b null mouse embryos show severe developmental arrest and usually die before embryonic day 9.5 (E9.5). Accumulation of cyclin E, a CRL (CUL4B) substrate, was observed in Cul4b null embryos. Cul4b heterozygotes were recovered at a reduced ratio and exhibited a severe developmental delay. The placentas in Cul4b heterozygotes were disorganized and were impaired in vascularization, which may contribute to the developmental delay. As in human CUL4B heterozygotes, Cul4b null cells were selected against in Cul4b heterozygotes, leading to various degrees of skewed X-inactivation in different tissues. Together, our results showed that CUL4B is indispensable for embryonic development in the mouse.