Characterization of a neural-specific splicing form of the human neuregulin 3 gene involved in oligodendrocyte survival
Characterization of a neural-specific splicing form of the human neuregulin 3 gene involved in oligodendrocyte survival
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DOI：
10.1242/jcs.02799
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发表时间：
2006-03-01
影响因子：
4
通讯作者：
Cabedo, H
中科院分区：
文献类型：
--
作者：
Carteron, C;Ferrer-Montiel, A;Cabedo, H
神经调节蛋白是一个涉及神经生物学关键方面的基因家族。神经调节蛋白1、2和3(NRG1、NRG2和NRG3)在哺乳动物的神经系统中表达。众所周知，NRG1具有15种不同的剪接形式，是核心的。对大脑发育和功能的影响。然而，NRG2和NRG3的生物学相关性仍然难以捉摸。在这里，我们报告了一种新的NRG3亚型的鉴定，该亚型在人类胚胎中枢神经系统中特异表达。与人类基因组的序列比对表明，该转录本是通过替代启动子使用而产生的。编码的多肽是一种I型糖基化的质膜蛋白，它被释放到细胞外空间，在那里激活ERBB4，ERBB4是大脑发育的关键受体。此外，我们还证明了该蛋白有一个信号序列，该序列在膜插入后被切割。用Lactacystin抑制蛋白酶体可以增强蛋白质的表达，而在条件突变细胞系TS20中泛素化的障碍则保护蛋白质免于降解。这些观察表明，泛素/蛋白酶体途径调节蛋白质的生物发生。我们还发现，重组神经调节蛋白3通过激活肌醇磷脂3-激酶信号通路，作为少突胶质细胞的生存因子。因此，我们报道了在发育中的人类中枢神经系统中表达的一种新的翻译后调节蛋白3亚型，它与少突胶质细胞的存活有关。
Neuregulins are a family of genes involved in key aspects of neural biology. Neuregulins 1, 2 and 3 (NRG1, NRG2 and NRG3) are expressed in the mammalian nervous system. It is well established that NRG1, with fifteen different splicing forms, is central. for brain development and function. However, the biological relevance of NRG2 and NRG3 remains elusive. Here, we report the identification of a new isoform of NRG3 that is specifically expressed in the human embryonic central nervous system. Sequence alignment with the human genome suggests that this transcript is produced by alternative promoter usage. The encoded polypeptide is a type-I-glycosylated plasma membrane protein, which is shed into the extracellular space where it activates erbB4, a pivotal receptor for brain development. In addition, we show that the protein has a signal sequence that is cleaved after membrane insertion. Proteasome inhibition with Lactacystin enhances the expression of the protein, whereas impairment of ubiquitylation in the conditional mutant cell line ts20 protects the protein from degradation. These observations imply that the ubiquitin/proteasome pathway regulates biogenesis of the protein. We also show that recombinant neuregulin 3 acts as an oligodendrocyte survival factor by activating the phosphoinositide 3-kinase signalling pathway. Therefore, we report a new post-translationally regulated isoform of neuregulin 3 expressed in the developing human central nervous system with a role in oligodendrocyte survival.