Disruption of the imprinted Grb10 gene leads to disproportionate overgrowth by an Igf2-independent mechanism
Disruption of the imprinted Grb10 gene leads to disproportionate overgrowth by an Igf2-independent mechanism
复制标题
DOI：
10.1073/pnas.1532175100
复制
发表时间：
2003-07-08
影响因子：
11.1
通讯作者：
Ward, A
中科院分区：
文献类型：
--
作者：
Charalambous, M;Smith, FM;Ward, A
为了研究Grb10衔接蛋白的功能，我们已经产生了Grb10基因被基因陷阱插入破坏的小鼠。我们的实验证实，Grb10是受基因组印迹与Grb10表达的大部分来自母系遗传的等位基因。与此相一致的是，母体等位基因的破坏导致胚胎和胎盘的过度生长，使得突变小鼠在出生时比正常小鼠大大约30%。这一观察结果表明Grb 10是一种有效的生长抑制剂。在人类中，GRB 10位于染色体7p11.2-p12，并与银罗素综合征有关，其中约10%的受影响者从母亲那里继承了两个7号染色体拷贝。我们的研究结果表明，GRB 10剂量的变化，至少在某些情况下，占严重的生长迟缓，是银罗素综合征的特征。由于Grb10是一种能够与酪氨酸激酶受体相互作用的信号蛋白，我们在遗传学上测试了Grb10是否可能在胰岛素样生长因子2（一种父系表达的生长促进基因）的下游起作用。结果表明，Grb10的行动基本上是独立的胰岛素样生长因子2，提供证据表明，印迹作用于至少两个主要的胎儿生长轴的方式与亲子冲突理论。
To investigate the function of the Grb10 adapter protein, we have generated mice in which the Grb10 gene was disrupted by a gene-trap insertion. Our experiments confirm that Grb10 is subject to genomic imprinting with the majority of Grb10 expression arising from the maternally inherited allele. Consistent with this, disruption of the maternal allele results in overgrowth of both the embryo and placenta such that mutant mice are at birth approximate to30% larger than normal. This observation establishes that Grb10 is a potent growth inhibitor. In humans, GRB10 is located at chromosome 7p11.2-p12 and has been associated with Silver-Russell syndrome, in which approximate to10% of those affected inherit both copies of chromosome 7 from their mother. Our results indicate that changes in GRB10 dosage could, in at least some cases, account for the severe growth retardation that is characteristic of Silver-Russell syndrome. Because Grb10 is a signaling protein capable of interacting with tyrosine kinase receptors, we tested genetically whether Grb10 might act downstream of insulin-like growth factor 2, a paternally expressed growth-promoting gene. The result indicates that Grb10 action is essentially independent of insulin-like growth factor 2, providing evidence that imprinting acts on at least two major fetal growth axes in a manner consistent with parent-offspring conflict theory.