Andrews Stuart C, Wood Michelle D, Tunster Simon J, Barton Sheila C, Surani M Azim, John Rosalind M
Cardiff School of Biosciences, Cardiff University, Cardiff, UK.
BMC Dev Biol. 2007 May 21;7:53. doi: 10.1186/1471-213X-7-53.
Cdkn1c encodes an embryonic cyclin-dependant kinase inhibitor that acts to negatively regulate cell proliferation and, in some tissues, to actively direct differentiation. This gene, which is an imprinted gene expressed only from the maternal allele, lies within a complex region on mouse distal chromosome 7, called the IC2 domain, which contains several other imprinted genes. Studies on mouse embryos suggest a key role for genomic imprinting in regulating embryonic growth and this has led to the proposal that imprinting evolved as a consequence of the mismatched contribution of parental resources in mammals.
In this study, we characterised the phenotype of mice carrying different copy number integrations of a bacterial artificial chromosome spanning Cdkn1c. Excess Cdkn1c resulted in embryonic growth retardation that was dosage-dependent and also responsive to the genetic background. Two-fold expression of Cdkn1c in a subset of tissues caused a 10-30% reduction in embryonic weight, embryonic lethality and was associated with a reduction in the expression of the potent, non-imprinted embryonic growth factor, Igf1. Conversely, loss of expression of Cdkn1c resulted in embryos that were 11% heavier with a two-fold increase in Igf1.
We have shown that embryonic growth in mice is exquisitely sensitive to the precise dosage of Cdkn1c. Cdkn1c is a maternally expressed gene and our findings support the prediction of the parental conflict hypothesis that that the paternal genome silences genes that have an inhibitory role in embryonic growth. Within the IC2 imprinted domain, Cdkn1c encodes the major regulator of embryonic growth and we propose that Cdkn1c was the focal point of the selective pressure for imprinting of this domain.
Cdkn1c编码一种胚胎期细胞周期蛋白依赖性激酶抑制剂，其作用是负向调节细胞增殖，并且在某些组织中积极引导分化。该基因是一个仅从母本等位基因表达的印记基因，位于小鼠7号远端染色体上一个称为IC2结构域的复杂区域内，该区域还包含其他几个印记基因。对小鼠胚胎的研究表明基因组印记在调节胚胎生长中起关键作用，这导致了一种观点，即印记的进化是哺乳动物中亲代资源贡献不匹配的结果。
在本研究中，我们对携带跨越Cdkn1c的细菌人工染色体不同拷贝数整合的小鼠的表型进行了表征。过量的Cdkn1c导致胚胎生长迟缓，这是剂量依赖性的，并且也对遗传背景有反应。Cdkn1c在一部分组织中的两倍表达导致胚胎重量减少10 - 30%、胚胎致死，并且与强效的、非印记的胚胎生长因子Igf1的表达减少有关。相反，Cdkn1c表达缺失导致胚胎重11%，Igf1增加两倍。
我们已经表明小鼠胚胎生长对Cdkn1c的精确剂量极其敏感。Cdkn1c是一个母本表达的基因，我们的发现支持了亲代冲突假说的预测，即父本基因组使对胚胎生长有抑制作用的基因沉默。在IC2印记结构域内，Cdkn1c编码胚胎生长的主要调节因子，我们提出Cdkn1c是该结构域印记选择压力的焦点。
