Muscleblind-like 2 knockout shifts adducin 1 isoform expression and alters dendritic spine dynamics of cortical neurons during brain development.

IF 4 2区医学 Q1 CLINICAL NEUROLOGY

Neuropathology and Applied Neurobiology Pub Date : 2023-04-01 DOI:10.1111/nan.12890

Chia-Wei Huang, Kuang-Yung Lee, Peng-Tzu Lin, Fang-Shin Nian, Haw-Yuan Cheng, Chien-Hui Chang, Cheng-Yen Liao, Yen-Lin Su, Carol Seah, Ching Li, Yu-Fu Chen, Mei-Hsuan Lee, Jin-Wu Tsai

引用次数: 1

Abstract

Muscleblind‐like 2 (MBNL2) plays a crucial role in regulating alternative splicing during development and mouse loss of MBNL2 recapitulates brain phenotypes in myotonic dystrophy (DM). However, the mechanisms underlying DM neuropathogenesis during brain development remain unclear. In this study, we aim to investigate the impact of MBNL2 elimination on neuronal development by Mbnl2 conditional knockout (CKO) mouse models.

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肌盲样2基因敲除可改变脑发育过程中皮质神经元的树突棘动力学。

目的:肌盲样2 (MBNL2)在发育过程中调节选择性剪接起着至关重要的作用，而小鼠MBNL2的缺失再现了肌强直性营养不良(DM)患者的大脑表型。然而，大脑发育过程中糖尿病神经发病机制尚不清楚。在这项研究中，我们旨在通过MBNL2条件敲除(CKO)小鼠模型研究MBNL2消除对神经元发育的影响。方法:通过子宫内电穿孔将编码crer -recombinase的cDNA导入Mbnl2flox/flox小鼠脑神经祖细胞，构建Mbnl2敲除神经元。用共聚焦和双光子显微镜观察了从新生儿期到成年期的脑切片和活体动物的树突棘的形态和动态。为了研究潜在的分子机制，我们进一步检测了与脊髓发生相关的蛋白质剪接和分子相互作用的变化。结果:我们发现皮质神经元Mbnl2敲除会降低青春期小鼠树突棘密度和动力学。Mbnl2消融导致内缩蛋白1 (ADD1)异构体通过移码从成人切换到胎儿，并且截断的ADD1无法与α - ii谱蛋白(SPTAN1)相互作用，SPTAN1是脊柱发生的关键蛋白。此外，ADD1成人亚型的表达弥补了MBNL2缺失皮质神经元中树突棘密度的降低。结论:MBNL2在维持脑发育过程中树突棘的动态和稳态中起关键作用。下游ADD1的错误剪接可能解释了改变，并有助于DM的脑发病机制。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Neuropathology and Applied Neurobiology 医学-病理学

CiteScore

8.20

自引率

2.00%

发文量

审稿时长

6-12 weeks

期刊介绍： Neuropathology and Applied Neurobiology is an international journal for the publication of original papers, both clinical and experimental, on problems and pathological processes in neuropathology and muscle disease. Established in 1974, this reputable and well respected journal is an international journal sponsored by the British Neuropathological Society, one of the world leading societies for Neuropathology, pioneering research and scientific endeavour with a global membership base. Additionally members of the British Neuropathological Society get 50% off the cost of print colour on acceptance of their article.