Rnf2 (Ring1b) deficiency causes gastrulation arrest and cell cycle inhibition
Rnf2 (Ring1b) deficiency causes gastrulation arrest and cell cycle inhibition
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DOI：
10.1073/pnas.0434312100
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发表时间：
2003-03-04
影响因子：
11.1
通讯作者：
van Lohuizen, M
中科院分区：
文献类型：
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作者：
Voncken, JW;Roelen, BAJ;van Lohuizen, M
高度同源的Rnf2 （Ring1b）和Ring1 （Ring1a）蛋白被鉴定为Polycomb Group （PcG）蛋白Bmi1的体内相互作用物。Rnf2的功能性消融导致原肠胚发育停滞，而其他大多数属于同一功能群的PcG基因无突变体的表型相对较轻，其中包括Ring1。发育缺陷发生在胚胎和胚胎外组织在原肠胚形成。早期致死表型让人想起PcG基因敲除ed和Ezh2，它们属于一个独立的功能PcG组和PcG蛋白复合物。这一发现表明，这些生物化学上不同的PcG复合物在小鼠早期发育过程中都是必需的。与Ring1半合子小鼠强烈的骨骼转化相反，Rnf2的半合子性不影响椎体的同一性。然而，它确实加重了Bmi1零突变背景下的小脑表型。总之，这些结果表明，尽管表达模式重叠，但Rnf2或含有ring1的PcG复合物在特定组织中具有最小的功能冗余。我们发现，在rnf2缺失的胚胎中，Cdkn2a （Ink4a/ARF）基因座的失活部分绕过了早期发育停滞。重要的是，这一发现暗示了polycomb介导的Cdkn2a基因座在早期小鼠发育中的抑制作用。
The highly homologous Rnf2 (Ring1b) and Ring1 (Ring1a) proteins were identified as in vivo interactors of the Polycomb Group (PcG) protein Bmi1. Functional ablation of Rnf2 results in gastrulation arrest, in contrast to relatively mild phenotypes in most other PcG gene null mutants belonging to the same functional group, among which is Ring1. Developmental defects occur in both embryonic and extraembryonic tissues during gastrulation. The early lethal phenotype is reminiscent of that of the PcG-gene knockouts Eed and Ezh2, which belong to a separate functional PcG group and PcG protein complex. This finding indicates that these biochemically distinct PcG complexes are both required during early mouse development. In contrast to the strong skeletal transformation in Ring1 hemizygous mice, hemizygocity for Rnf2 does not affect vertebral identity. However, it does aggravate the cerebellar phenotype in a Bmi1 null-mutant background. Together, these results suggest that Rnf2 or Ring1-containing PcG complexes have minimal functional redundancy in specific tissues, despite overlap in expression patterns. We show that the early developmental arrest in Rnf2-null embryos is partially bypassed by genetic inactivation of the Cdkn2a (Ink4a/ARF) locus. importantly, this finding implicates Polycomb-mediated repression of the Cdkn2a locus in early murine development.