IKAP deficiency in an FD mouse model and in oligodendrocyte precursor cells results in downregulation of genes involved in oligodendrocyte differentiation and myelin formation.
IKAP deficiency in an FD mouse model and in oligodendrocyte precursor cells results in downregulation of genes involved in oligodendrocyte differentiation and myelin formation.
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DOI：
10.1371/journal.pone.0094612
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Razin A
中科院分区：
文献类型：
--
作者：
Cheishvili D;Dietrich P;Maayan C;Even A;Weil M;Dragatsis I;Razin A
编码IKAP蛋白的IKBKAP基因的剪接位点突变导致组织特异性外显子20的跳变，同时IKAP蛋白的产生减少。这导致神经发育，常染色体隐性遗传疾病-家族性自主神经异常（FD）。FD的分子特征是神经系统中IKAP蛋白的严重减少，这被认为是该疾病破坏性症状的主要原因。我们最近的研究表明，在两例FD患者的大脑中，与少突胶质细胞分化和/或髓鞘形成相关的基因显著下调，暗示IKAP参与髓鞘形成过程。然而，由于FD患者组织的稀缺性，这些结果有待于在其他模型中进一步验证。最近，两种忠实再现FD的FD小鼠模型被生成，两种类型的突变导致IKAP表达严重低水平。在这里，我们证明这些FD小鼠模型中的IKAP缺陷影响了与FD患者大脑中相似的一组基因。此外，我们发现了两个新的IKAP靶基因参与少突胶质细胞分化和髓鞘形成，进一步强调了IKAP在这一过程中的重要作用。我们还提供了证据，证明IKAP的表达是细胞自主调节髓磷脂形成相关基因表达所必需的，因为在oli - new少突胶质前体细胞中IKAP的敲低会导致类似的缺陷。对这两种实验模型的进一步分析将弥补人类死后组织的不足，并将促进我们对IKAP在髓鞘形成和疾病病理中的作用的理解。
The splice site mutation in the IKBKAP gene coding for IKAP protein leads to the tissue-specific skipping of exon 20, with concomitant reduction in IKAP protein production. This causes the neurodevelopmental, autosomal-recessive genetic disorder - Familial Dysautonomia (FD). The molecular hallmark of FD is the severe reduction of IKAP protein in the nervous system that is believed to be the main reason for the devastating symptoms of this disease. Our recent studies showed that in the brain of two FD patients, genes linked to oligodendrocyte differentiation and/or myelin formation are significantly downregulated, implicating IKAP in the process of myelination. However, due to the scarcity of FD patient tissues, these results awaited further validation in other models. Recently, two FD mouse models that faithfully recapitulate FD were generated, with two types of mutations resulting in severely low levels of IKAP expression. Here we demonstrate that IKAP deficiency in these FD mouse models affects a similar set of genes as in FD patients' brains. In addition, we identified two new IKAP target genes involved in oligodendrocyte cells differentiation and myelination, further underscoring the essential role of IKAP in this process. We also provide proof that IKAP expression is needed cell-autonomously for the regulation of expression of genes involved in myelin formation since knockdown of IKAP in the Oli-neu oligodendrocyte precursor cell line results in similar deficiencies. Further analyses of these two experimental models will compensate for the lack of human postmortem tissues and will advance our understanding of the role of IKAP in myelination and the disease pathology.
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影响因子：
3.1
作者：
Cuajungco, MP;Leyne, M;Slaugenhaupt, SA
通讯作者：
Slaugenhaupt, SA
影响因子：
3.5
作者：
Bochner, Ron;Ziv, Yael;Ast, Gil
通讯作者：
Ast, Gil
影响因子：
6.2
作者：
Ganfornina, Maria D.;Do Carmo, Sonia;Sanchez, Diego
通讯作者：
Sanchez, Diego
影响因子：
9.8
作者：
Cuajungco, MP;Leyne, M;Slaugenhaupt, SA
通讯作者：
Slaugenhaupt, SA
影响因子：
4.4
作者：
Hims, Matthew M.;Shetty, Ranjit S.;Slaugenhaupt, Susan A.
通讯作者：
Slaugenhaupt, Susan A.