Non-imprinted Igf2r expression decreases growth and rescues the Tme mutation in mice.
Non-imprinted Igf2r expression decreases growth and rescues the Tme mutation in mice.
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DOI：
10.1242/dev.128.10.1881
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发表时间：
2001-05
期刊：
影响因子：
4.6
通讯作者：
A. Wutz;H. Theussl;J. Dausman;R. Jaenisch;D. Barlow;E. Wagner
中科院分区：
文献类型：
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作者：
A. Wutz;H. Theussl;J. Dausman;R. Jaenisch;D. Barlow;E. Wagner
在小鼠中，胰岛素样生长因子受体2型基因（Igf 2 r）是印记和母系表达的。igf 2 r编码一种跨膜受体，将甘露糖-6-磷酸标记的蛋白质和胰岛素样生长因子2转运到溶酶体。在发育过程中，受体减少胰岛素样生长因子的量，从而降低胚胎生长。该基因的剂量受到基因组印记的严格调控，只留下该基因的母体拷贝。虽然Igf 2 r在发育中的功能已经得到了很好的证实，但印记基因的功能仍然难以捉摸。小鼠中的基因靶向实验已经证明，大多数基因对基因剂量不敏感，并且突变杂合子小鼠通常缺乏表型改变。为了研究通过基因组印记减少Igf 2 r基因剂量是否对发育具有功能性后果，我们产生了非印记等位基因（R2 Delta）。我们通过删除小鼠胚胎干细胞中抑制父系等位基因（区域2）的关键元件来恢复Igf 2 r的双等位基因表达。R2 Delta等位基因的母系遗传没有表型;然而，父系遗传导致Igf 2 r的双等位基因表达，这导致胚胎发育后期体重减轻20%，并持续到成年期。R2 Delta等位基因的父系遗传挽救了母系遗传的Igf 2 r无效等位基因和母系遗传的Tme（T相关的母系效应）突变的致死性。这些数据表明，印迹Igf 2 r的生物学功能是增加出生体重，他们也建立了Igf 2 r作为Tme基因。
In the mouse the insulin-like growth factor receptor type 2 gene (Igf2r) is imprinted and maternally expressed. Igf2r encodes a trans-membrane receptor that transports mannose-6-phosphate tagged proteins and insulin-like growth factor 2 to lysosomes. During development the receptor reduces the amount of insulin-like growth factors and thereby decreases embryonic growth. The dosage of the gene is tightly regulated by genomic imprinting, leaving only the maternal copy of the gene active. Although the function of Igf2r in development is well established, the function of imprinting the gene remains elusive. Gene targeting experiments in mouse have demonstrated that the majority of genes are not sensitive to gene dosage, and mice heterozygous for mutations generally lack phenotypic alterations. To investigate whether reduction of Igf2r gene dosage by genomic imprinting has functional consequences for development we generated a non-imprinted allele (R2Delta). We restored biallelic expression to Igf2r by deleting a critical element for repression of the paternal allele (region 2) in mouse embryonic stem cells. Maternal inheritance of the R2Delta allele has no phenotype; however, paternal inheritance results in biallelic expression of Igf2r, which causes a 20% reduction in weight late in embryonic development that persists into adulthood. Paternal inheritance of the R2Delta allele rescues the lethality of a maternally inherited Igf2r null allele and a maternally inherited Tme (T-associated maternal effect) mutation. These data show that the biological function of imprinting Igf2r is to increase birth weight and they also establish Igf2r as the Tme gene.