BACKGROUND Formation and maintenance of appropriate neural networks require tight regulation of neural stem cell proliferation, differentiation, and neurogenesis. microRNAs (miRNAs) play an important role in brain development and plasticity, and dysregulated miRNA profiles have been linked to neurodevelopmental disorders including autism, schizophrenia, or intellectual disability. Yet, the functional role of miRNAs in neural development and postnatal brain functions remains unclear. METHODS Using a combination of cell biology techniques as well as behavioral studies and brain imaging, we characterize mouse models with either constitutive inactivation or selectively hippocampal knockdown of the neurodevelopmental disease-associated gene Mir146a, the most commonly deregulated miRNA in developmental brain disorders (DBD). RESULTS We first show that during development, loss of miR-146a impairs the differentiation of radial glial cells, neurogenesis process, and neurite extension. In the mouse adult brain, loss of miR-146a correlates with an increased hippocampal asymmetry coupled with defects in spatial learning and memory performances. Moreover, selective hippocampal downregulation of miR-146a in adult mice causes severe hippocampal-dependent memory impairments indicating for the first time a role for this miRNA in postnatal brain functions. CONCLUSION Our results show that miR-146a expression is critical for correct differentiation of neural stem cell during brain development and provide for the first time a strong argument for a postnatal role of miR-146a in regulating hippocampal-dependent memory. Furthermore, the demonstration that the Mir146a-/- mouse recapitulates several aspects reported in DBD patients, including impaired neurogenesis, abnormal brain anatomy, and working and spatial memories deficits, provides convincing evidence that the dysregulation of miR146a contributes to the pathogenesis of DBDs.

中文翻译：

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神经发育疾病相关基因 miR-146a 的缺失会损害神经祖细胞分化并导致学习和记忆缺陷。


背景技术适当的神经网络的形成和维持需要对神经干细胞增殖、分化和神经发生的严格调节。 microRNA (miRNA) 在大脑发育和可塑性中发挥着重要作用，失调的 miRNA 谱与神经发育障碍（包括自闭症、精神分裂症或智力障碍）有关。然而，miRNA 在神经发育和出生后大脑功能中的功能作用仍不清楚。方法结合细胞生物学技术以及行为研究和脑成像，我们表征了神经发育疾病相关基因 Mir146a 的组成性失活或选择性海马敲低的小鼠模型，Mir146a 是发育性脑疾病 (DBD) 中最常见的失调 miRNA 。结果我们首先表明，在发育过程中，miR-146a 的缺失会损害放射状胶质细胞的分化、神经发生过程和神经突延伸。在成年小鼠大脑中，miR-146a 的缺失与海马不对称性增加以及空间学习和记忆表现缺陷相关。此外，成年小鼠海马区 miR-146a 的选择性下调会导致严重的海马依赖性记忆障碍，这首次表明该 miRNA 在出生后大脑功能中的作用。结论 我们的结果表明，miR-146a 表达对于大脑发育过程中神经干细胞的正确分化至关重要，并首次为 miR-146a 在调节海马依赖性记忆中的出生后作用提供了有力的论据。 此外，Mir146a-/-小鼠重现了 DBD 患者报告的几个方面，包括神经发生受损、大脑解剖异常以及工作和空间记忆缺陷，这提供了令人信服的证据，证明 miR146a 的失调有助于 DBD 的发病机制。