Mammalian TRIM67 Functions in Brain Development and Behavior.
Mammalian TRIM67 Functions in Brain Development and Behavior.
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哺乳动物TRIM67在大脑发育和行为中起作用。
DOI：
10.1523/eneuro.0186-18.2018
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发表时间：
2018-05
期刊：
影响因子：
3.4
通讯作者：
Gupton SL
中科院分区：
文献类型：
--
作者：
Boyer NP;Monkiewicz C;Menon S;Moy SS;Gupton SL
E3泛素连接酶的tripartite motif （TRIM）家族的第一类成员在进化上出现在神经元样细胞出现之前，并与从无脊椎动物到哺乳动物的神经元发育有关。黑腹果蝇和秀丽隐杆线虫的单一I类TRIM和哺乳动物的I类TRIM9响应引导线索网络调节轴突分支和引导，而哺乳动物的TRIM46则建立轴突初始段。在人类中，TRIM1和TRIM18的突变与Opitz综合征有关，该综合征以中线缺陷和智力残疾为特征。我们发现，尽管TRIM67是被研究最少的I类TRIM脊椎动物，但它在进化上是最保守的。在这里，我们发现哺乳动物TRIM67与其最接近的同类TRIM9和网络蛋白受体DCC相互作用，并在发育和成年期间在特定的大脑区域中不同地富集。我们描述了小鼠Trim67缺失的解剖学和行为学后果。在存活的情况下，缺乏Trim67的小鼠在特定的大脑区域表现出异常的解剖结构，包括海马、纹状体、杏仁核和丘脑的萎缩，以及前脑连接的变薄。此外，Trim67 - / -小鼠在空间记忆、认知灵活性、社会新奇偏好、肌肉功能和感觉运动门控方面表现出损伤，而其他一些行为保持不变。这项研究证明了TRIM67在适当的大脑发育和行为中的必要性。
Class I members of the tripartite motif (TRIM) family of E3 ubiquitin ligases evolutionarily appeared just prior to the advent of neuronal like cells and have been implicated in neuronal development from invertebrates to mammals. The single Class I TRIM in Drosophila melanogaster and Caenorhabditis elegans and the mammalian Class I TRIM9 regulate axon branching and guidance in response to the guidance cue netrin, whereas mammalian TRIM46 establishes the axon initial segment. In humans, mutations in TRIM1 and TRIM18 are implicated in Opitz Syndrome, characterized by midline defects and often intellectual disability. We find that although TRIM67 is the least studied vertebrate Class I TRIM, it is the most evolutionarily conserved. Here we show that mammalian TRIM67 interacts with both its closest paralog TRIM9 and the netrin receptor DCC and is differentially enriched in specific brain regions during development and adulthood. We describe the anatomical and behavioral consequences of deletion of murine Trim67. While viable, mice lacking Trim67 exhibit abnormal anatomy of specific brain regions, including hypotrophy of the hippocampus, striatum, amygdala, and thalamus, and thinning of forebrain commissures. Additionally, Trim67−/− mice display impairments in spatial memory, cognitive flexibility, social novelty preference, muscle function, and sensorimotor gating, whereas several other behaviors remain intact. This study demonstrates the necessity for TRIM67 in appropriate brain development and behavior.