神经干细胞发育障碍与孤独症有关

tanhin

http://life.lifesci.cn/html/2008-07/6150.htm

http://www.eph.org.cn/ReadNews.asp?NewsID=15697



PNAS：神经干细胞发育障碍与孤独症有关

    生命科学动态 报道：美国科学家近日研究发现，神经干细胞发育障碍与孤独症有关。研究证实，神经干细胞缺乏肌细胞增强子2C（MEF2C）的小鼠具有较小的大脑、更少的神经细胞，并表现出与雷特氏综合症（Rett Syndrome，孤独症的一种）患者相类似的行为。相关论文6月30日发表在美国《国家科学院院刊》（PNAS）上。

    领导此次研究的是美国伯恩汉医学研究所的Stuart A. Lipton。研究人员发现，MEF2C会开启特殊的基因，这些基因驱动干细胞分化成神经细胞。当从小鼠的神经干细胞中删除MEF2C后，会出现神经细胞的错误“分配”，并伴有严重的发育问题。脑部缺乏MEF2C的成年小鼠会表现出反常的焦虑行为，认知能力下降，爪紧抓，这与患有雷特氏综合症的人搓手的显著特征相类似。

    此次研究首次提出，神经干细胞发育障碍与并发的孤独症之间存在直接联系。Lipton说：“此次结果为我们提供了很好的线索来研究雷特氏综合症和潜在的其它人类孤独症。识别出导致这种缺陷的变异后，我们能够追踪所发生的情况。也许我们能够在小鼠身上进行纠正，假如成功的话，最终也可能在人类身上实现。”

Syntrophin mutation associated with long QT syndrome through activation of the nNOS–SCN5A macromo lecular complex

Abstract

Mutations in 11 genes that encode ion channels or their associated proteins cause inherited long QT syndrome (LQTS) and account for 75–80% of cases (LQT1–11). Direct sequencing of SNTA1, the gene encoding 1-syntrophin, was performed in a cohort of LQTS patients that were negative for mutations in the 11 known LQTS-susceptibility genes. A missense mutation (A390V-SNTA1) was found in a patient with recurrent syncope and markedly prolonged QT interval (QTc, 530 ms). SNTA1 links neuronal nitric oxide synthase (nNOS) to the nNOS inhibitor plasma membrane Ca-ATPase subtype 4b (PMCA4b); SNTA1 also is known to associate with the cardiac sodium channel SCN5A. By using a GST-fusion protein of the C terminus of SCN5A, we showed that WT-SNTA1 interacted with SCN5A, nNOS, and PMCA4b. In contrast, A390V-SNTA1 selectively disrupted association of PMCA4b with this complex and increased direct nitrosylation of SCN5A. A390V-SNTA1 expressed with SCN5A, nNOS, and PMCA4b in heterologous cells increased peak and late sodium current compared with WT-SNTA1, and the increase was partially inhibited by NOS blockers. Expression of A390V-SNTA1 in cardiac myocytes also increased late sodium current. We conclude that the A390V mutation disrupted binding with PMCA4b, released inhibition of nNOS, caused S-nitrosylation of SCN5A, and was associated with increased late sodium current, which is the characteristic biophysical dysfunction for sodium-channel-mediated LQTS (LQT3). These results establish an SNTA1-based nNOS complex attached to SCN5A as a key regulator of sodium current and suggest that SNTA1 be considered a rare LQTS-susceptibility gene.

秋爸爸

摘要应为：

Proc Natl Acad Sci U S A. 2008 Jul 1. [Epub ahead of print]

Transcription factor MEF2C influences neural stem/progenitor cell differentiation and maturation in vivo.

Li H, ..... Lipton SA.

Center for Neuroscience, Aging, and Stem Cell Research, Burnham Institute for Medical Research, La Jolla, CA 92037;

Abstract
Emerging evidence suggests that myocyte enhancer factor 2 (MEF2) transcription factors act as effectors of neurogenesis in the brain, with MEF2C the predominant isoform in developing cerebrocortex. Here, we show that conditional knockout of Mef2c in nestin-expressing neural stem/progenitor cells (NSCs) impaired neuronal differentiation in vivo, resulting in aberrant compaction and smaller somal size. NSC proliferation and survival were not affected. Conditional null mice surviving to adulthood manifested more immature electrophysiological network properties and severe behavioral deficits reminiscent of Rett syndrome, an autism-related disorder. Our data support a crucial role for MEF2C in programming early neuronal differentiation and proper distribution within the layers of the neocortex.

full text:
http://www.pnas.org/content/105/27/9397

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