PREMATURE ARREST OF MYELIN FORMATION IN TRANSGENIC MICE WITH INCREASED PROTEOLIPID PROTEIN GENE DOSAGE
PREMATURE ARREST OF MYELIN FORMATION IN TRANSGENIC MICE WITH INCREASED PROTEOLIPID PROTEIN GENE DOSAGE
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DOI：
10.1016/0896-6273(94)90214-3
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发表时间：
1994-03-01
期刊：
影响因子：
16.2
通讯作者：
NAVE, KA
中科院分区：
文献类型：
--
作者：
READHEAD, C;SCHNEIDER, A;NAVE, KA
蛋白脂蛋白（PLP）是中枢神经系统髓磷脂的一种完整膜蛋白。X染色体相关的PLP基因突变会导致神经胶质细胞死亡和髓磷脂缺乏。作为通过转基因互补挽救这些突变体的尝试的一部分，我们产生了表达整个野生型PLP基因常染色体拷贝的正常小鼠系。令人惊讶的是，在只有2倍转录过表达的非突变小鼠中，PLP基因剂量的增加会导致一种新的表型，其特征是严重的髓鞘退化和星形细胞增多，癫痫发作和过早死亡。这表明精确控制PLP基因是终端少突胶质细胞分化的关键决定因素。PLP转基因小鼠的髓鞘发育异常提供了实验证据，表明先前与人类X染色体部分重复相关的Pelizaeus-Merzbacher病可由PLP基因剂量加倍引起。
Proteolipid protein (PLP) is an integral membrane protein of CNS myelin. Mutations of the X chromosome-linked PLP gene cause glial cell death and myelin deficiency in jimpy mice and other neurological mutants. As part of an attempt to rescue these mutants by transgenic complementation, we generated normal mouse lines expressing autosomal copies of the entire wild-type PLP gene. Surprisingly, increase of the PLP gene dosage in nonmutant mice with only 2-fold transcriptional overexpression results in a novel phenotype characterized by severe hypomyelination and astrocytosis, seizures, and premature death. This demonstrates that precise control of the PLP gene is a critical determinant of terminal oligodendrocyte differentiation. Dysmyelination of PLP transgenic mice provides experimental evidence that Pelizaeus-Merzbacher disease, previously associated with a partial duplication of the human X chromosome, can be caused by doubling of the PLP gene dosage.