Roles of the imprinted gene Igf2 and paternal duplication of distal chromosome 7 in the perinatal abnormalities of androgenetic mouse chimeras.
Roles of the imprinted gene Igf2 and paternal duplication of distal chromosome 7 in the perinatal abnormalities of androgenetic mouse chimeras.
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发表时间：
1997-12
期刊：
影响因子：
4.6
通讯作者：
K. McLaughlin;H. Kochanowski;D. Solter;G. Schwarzkopf;P. Szabó;J. Mann
中科院分区：
文献类型：
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作者：
K. McLaughlin;H. Kochanowski;D. Solter;G. Schwarzkopf;P. Szabó;J. Mann
由雄激素（两个父亲基因组）卵子或胚胎干细胞制成的小鼠嵌合体经常在围产期死亡，并表现出一系列缺陷，最值得注意的是肋软骨明显过度生长。过量浓度的IGFII（一种有效的有丝分裂原）被认为在这些缺陷中起主要作用，因为雄激素发生细胞具有两个活性的印迹Igf 2基因的父系拷贝，而不是正常细胞中的一个非活性的母系和一个活性的父系拷贝。在这里，我们表明，嵌合体与雄激素胚胎干细胞，纯合子的Igf 2无效突变，不发展肋软骨增生，证明这种缺陷的依赖性，由雄激素细胞产生的Igf 2活性。相反，在这些相同的嵌合体中，许多其他缺陷，包括全身过度生长和围产期死亡，仍然普遍存在，表明一个或多个印迹基因的异常表达，而不是Igf 2，也能够诱导雄激素嵌合体的大多数缺陷。这些基因中的许多可能位于远端7号染色体上，因为我们还表明，围产期嵌合体与胚胎干细胞具有远端7号染色体的父系复制表现出一系列类似于雄激素嵌合体的缺陷。这些研究结果的相关性的人类印记相关的疾病，贝克威-威德曼综合征，进行了讨论。
Mouse chimeras made with androgenetic (two paternal genomes) ova or embryonic stem cells frequently die at the perinatal stage and exhibit a range of defects, the most noticeable being a pronounced overgrowth of rib cartilage. Excess concentrations of IGFII, a potent mitogen, has been suggested to play a major role in these defects, as androgenetic cells possess two active paternal copies of the imprinted Igf2 gene, rather than one inactive maternal and one active paternal copy as in normal cells. Here, we show that chimeras made with androgenetic embryonic stem cells, homozygous for an Igf2 null mutation, do not develop rib cartilage hyperplasia, demonstrating the dependence of this defect on Igf2 activity produced by androgenetic cells. In contrast, in these same chimeras, many other defects, including whole body overgrowth and perinatal death, are still prevalent, indicating that the abnormal expression of one or more imprinted genes, other than Igf2, is also capable of inducing most of the defects of androgenetic chimeras. Many of these genes may reside on distal chromosome 7, as we also show that perinatal chimeras made with embryonic stem cells possessing paternal duplication of distal chromosome 7 exhibit a range of defects similar to those of androgenetic chimeras. The relevance of these findings for the human imprinting-related disorder, Beckwith-Wiedemann syndrome, is discussed.