Division of Biology, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, United States of America.
PLoS Genet. 2010 Jan;6(1):e1000803. doi: 10.1371/journal.pgen.1000803. Epub 2010 Jan 8.
The misexpressed imprinted genes causing developmental failure of mouse parthenogenones are poorly defined. To obtain further insight, we investigated misexpressions that could cause the pronounced growth deficiency and death of fetuses with maternal duplication of distal chromosome (Chr) 7 (MatDup.dist7). Their small size could involve inactivity of Igf2, encoding a growth factor, with some contribution by over-expression of Cdkn1c, encoding a negative growth regulator. Mice lacking Igf2 expression are usually viable, and MatDup.dist7 death has been attributed to the misexpression of Cdkn1c or other imprinted genes. To examine the role of misexpressions determined by two maternal copies of the Igf2/H19 imprinting control region (ICR)-a chromatin insulator, we introduced a mutant ICR (ICR(Delta)) into MatDup.dist7 fetuses. This activated Igf2, with correction of H19 expression and other imprinted transcripts expected. Substantial growth enhancement and full postnatal viability was obtained, demonstrating that the aberrant MatDup.dist7 phenotype is highly dependent on the presence of two unmethylated maternal Igf2/H19 ICRs. Activation of Igf2 is likely the predominant correction that rescued growth and viability. Further experiments involved the introduction of a null allele of Cdkn1c to alleviate its over-expression. Results were not consistent with the possibility that this misexpression alone, or in combination with Igf2 inactivity, mediates MatDup.dist7 death. Rather, a network of misexpressions derived from dist7 is probably involved. Our results are consistent with the idea that reduced expression of IGF2 plays a role in the aetiology of the human imprinting-related growth-deficit disorder, Silver-Russell syndrome.
导致小鼠孤雌生殖胚胎发育失败的印迹基因表达异常尚不清楚。为了进一步深入了解，我们研究了可能导致具有母源 7 号染色体（Chr7）重复（MatDup.dist7）的胎儿明显生长缺陷和死亡的表达异常。它们的体积较小可能涉及生长因子编码基因 Igf2 的失活，以及生长负调控因子编码基因 Cdkn1c 的过度表达。缺乏 Igf2 表达的小鼠通常是有活力的，而 MatDup.dist7 的死亡归因于 Cdkn1c 或其他印迹基因的表达异常。为了研究由 Igf2/H19 印迹控制区（ICR）的两个母本拷贝决定的表达异常的作用——一种染色质绝缘子，我们将突变的 ICR（ICR(Delta)）引入 MatDup.dist7 胎儿中。这激活了 Igf2，预期可以纠正 H19 的表达和其他印迹转录本。获得了显著的生长增强和完全的产后生存能力，表明异常的 MatDup.dist7 表型高度依赖于两个未甲基化的母本 Igf2/H19 ICR 的存在。Igf2 的激活可能是挽救生长和活力的主要校正。进一步的实验涉及引入 Cdkn1c 的 null 等位基因以减轻其过度表达。结果与这种表达异常单独或与 Igf2 失活相结合介导 MatDup.dist7 死亡的可能性不一致。相反，可能涉及源自 dist7 的一系列表达异常。我们的结果与 IGF2 表达减少在人类印迹相关生长缺陷疾病 Silver-Russell 综合征的发病机制中起作用的观点一致。
