An ancient duplication of exon 5 in the Snap25 gene is required for complex neuronal development/function.
An ancient duplication of exon 5 in the Snap25 gene is required for complex neuronal development/function.
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DOI：
10.1371/journal.pgen.1000278
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发表时间：
2008-11
期刊：
影响因子：
4.5
通讯作者：
Bark C
中科院分区：
文献类型：
--
作者：
Johansson JU;Ericsson J;Janson J;Beraki S;Stanić D;Mandic SA;Wikström MA;Hökfelt T;Ogren SO;Rozell B;Berggren PO;Bark C
选择性剪接是一种进化创新，从有限数量的基因中产生功能多样的蛋白质。SNAP-25通过在调节的胞吐作用期间将突触囊泡桥接至质膜而在神经胞吐作用中起中心作用。SNAP-25多肽由单拷贝基因编码，但在高等脊椎动物中，外显子5的重复导致两个互斥的剪接变体SNAP-25 a和SNAP-25 b。为了解决两种SNAP-25蛋白之间的潜在生理差异，我们通过用第二SNAP-25 a等同物替换SNAP-25 b特异性外显子来产生基因靶向的SNAP-25 b缺陷型小鼠突变体。SNAP-25 b表达的消除导致发育缺陷、自发性癫痫发作和短期突触可塑性受损。在成年突变体中，海马的形态学变化和神经肽表达的急剧变化伴随着严重的空间学习障碍。我们的结论是，古老的外显子重复的Snap 25基因提供了额外的SNAP-25功能所需的复杂的神经元过程在高等真核生物。在进化过程中，基因或基因片段的复制似乎是在更复杂的生物体中增加多种功能的有效方法。SNAP-25蛋白在介导神经递质和激素的释放中起重要作用。SNAP-25存在两种变体：SNAP-25 a，存在于早期发育中，SNAP-25 b，从成年早期开始最丰富。我们已经开发出只表达SNAP-25 a的小鼠突变体，但通过用额外的SNAP-25 a拷贝替换Snap 25基因中的SNAP-25 b片段来保持正常的SNAP-25水平。我们表明，SNAP-25 b是出生后早期发育所必需的，这两种蛋白质的平衡表达是维持成年期神经元网络运作的先决条件。只有SNAP-25 a的小鼠会出现癫痫发作，并表现出学习缺陷和焦虑。突触可塑性受损，在与这些行为功能相关的区域观察到结构变化。在人类中，SNAP-25功能与行为和神经精神障碍有关，包括注意力缺陷多动障碍，ADHD。我们目前使用SNAP-25 b基因消除的研究结果表明，即使是Snap 25基因调控的微小改变，导致SNAP-25 a和SNAP-25 b之间的平衡失调，也会导致神经系统功能障碍。
Alternative splicing is an evolutionary innovation to create functionally diverse proteins from a limited number of genes. SNAP-25 plays a central role in neuroexocytosis by bridging synaptic vesicles to the plasma membrane during regulated exocytosis. The SNAP-25 polypeptide is encoded by a single copy gene, but in higher vertebrates a duplication of exon 5 has resulted in two mutually exclusive splice variants, SNAP-25a and SNAP-25b. To address a potential physiological difference between the two SNAP-25 proteins, we generated gene targeted SNAP-25b deficient mouse mutants by replacing the SNAP-25b specific exon with a second SNAP-25a equivalent. Elimination of SNAP-25b expression resulted in developmental defects, spontaneous seizures, and impaired short-term synaptic plasticity. In adult mutants, morphological changes in hippocampus and drastically altered neuropeptide expression were accompanied by severe impairment of spatial learning. We conclude that the ancient exon duplication in the Snap25 gene provides additional SNAP-25-function required for complex neuronal processes in higher eukaryotes. In evolution, duplication of genes or gene segments appears to be an efficient way to add diverse functions in more complex organisms. The SNAP-25 protein plays an important role in mediating the release of neurotransmitters and hormones. SNAP-25 exists as two variants: SNAP-25a, which is present in early development, and SNAP-25b, which is most abundant from early adulthood and onwards. We have developed mouse mutants that only express SNAP-25a, but retain normal SNAP-25 levels by replacing the SNAP-25b segment in the Snap25 gene with an additional SNAP-25a copy. We show that SNAP-25b is required for early postnatal development and that a balanced expression of the two proteins is a prerequisite for maintaining an operational neuronal network during adulthood. Mice that only have SNAP-25a develop seizures, and show learning deficits and anxiety. Synaptic plasticity is impaired, and structural changes are observed in areas that are connected to such behavioral functions. In man, SNAP-25 function has been linked to behavioral and neuropsychiatric disorders, including attention deficit hyperactivity disorder, ADHD. Our present findings using genetic elimination of SNAP-25b suggest that even small alterations in the regulation of the Snap25 gene, resulting in a disturbed balance between SNAP-25a and SNAP-25b, lead to nervous system dysfunction.
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影响因子：
5.6
作者：
BARK, IC
通讯作者：
BARK, IC
影响因子：
5.3
作者：
Delgado-Martinez, Ignacio;Nehring, Ralf B.;Sorensen, Jakob B.
通讯作者：
Sorensen, Jakob B.
影响因子：
5.5
作者：
CHARLTON, MP;SMITH, SJ;ZUCKER, RS
通讯作者：
ZUCKER, RS
影响因子：
56.9
作者：
BENNETT, MK;CALAKOS, N;SCHELLER, RH
通讯作者：
SCHELLER, RH
影响因子：
5.5
作者：
KATZ, B;MILEDI, R
通讯作者：
MILEDI, R