m 6A 修饰调控小鼠大脑皮层 神经发育的机制研究

m6A 是一种在 mRNA 和非编码 RNAs 中广泛存在的动态且可逆的甲基化
修饰， m6A 修饰在干细胞增殖与分化、癌症发生、神经发育、神经环路形成
等过程中有着重要调控作用。然而目前为止 m6A 修饰调控神经系统的研究主
要集中于其甲基化酶即‘writers’和去甲基化酶即‘erasers’， 而对其阅读器蛋白
即‘readers’是如何调控特定基因的表达从而调控神经系统的功能与机制所知
甚少。本课题利用小鼠大脑皮层神经系统，主要通过免疫荧光、 条件性敲除
小鼠表型分析、 体外原代神经细胞培养、 细胞增殖和分化分析等手段研究
m6A 的阅读器蛋白 YTHDF1、 YTHDF2 在大脑皮层发育中的时空表达谱与功
能。 我们得到了 YTHDF1、 YTHDF2 在小鼠大脑皮层内的表达谱；针对
YTHDF1 与 YTHDF2 蛋白功能，我们初步分析了 Emx1-cre+/-,Ythdf1fl/fl；
Emx1-cre+/-,Ythdf2fl/fl； Nestin-cre+/-,Ythdf1 fl/fl； Nestin-cre+/-,Ythdf2fl/fl 四种 cKO
小鼠的大脑皮层在发育过程中与对照组相比皮层厚度的变化； 建立了大脑皮
层体外细胞培养体系并进行 EdU 实验研究 m6A 修饰对细胞增殖的影响； 且
对后续实验中继续深一步研究 m6A 修饰在小鼠大脑皮层神经发育中的功能
与具体调控机制提供了合理、可行的实验方案。 我们的实验结果证明了
YTHDF2 在小鼠大脑皮层神经发育中存在重要的调控作用，初步分析结果显
示条件性敲除 YTHDF2 仔鼠的大脑皮层显著变薄；在领域内现有研究结果的
基础上， 本课题对 m6A 修饰在小鼠大脑皮层神经发生过程中的功能与调控机
制进行了进一步的解析。尤其对 YTHDF2 参与的 m6A 调控过程， 我们计划
在后续实验中得到较完整的调控机制，对研究 m6A 在神经系统发育与功能等
方面提供重要参考依据。
 

N6-methyladenosine (m6A) is a dynamic and reversible modification in
mRNA and non-coding RNAs, and has been shown to regulate the proliferation
and differentiation in stem cells, tumorigenesis, neurodevelopment and nerve
circuit formation. However, current studies on m6A modification mediating nerve
system mainly have been focusing on its ‘writers’ and ‘erasers’. How m6A
‘readers’ regulate neurodevelopment by targeting specific neural target mRNAs
is still unclear. In this project, using mouse cerebral cortex system, we studied
expression patterns of m6A readers YTHDF1, YTHDF2 proteins and functions of
YTHDF1,YTHDF2 in cortex neurogenesis in vivo and in vitro by
immunofluorescence, conditional knockout mice phenotype analysis, primary
neuron culture, cell proliferation assay. Firstly, we checked expression patterns
of YTHDF1 and YTHDF2 in mouse cortex in different developmental stages.
Then we analyzed the cortical tissues in conditional knockout mice, and we
found that YTHDF2 could play an important role in cortical neurogenesis
because preliminary results have shown that the cortical thickness in cKO
embryos is significantly decreased compared with littermate controls. Thirdly,
we cultured embryonic primary cortical neurons and carried out EdU assay to
check the cell proliferation. Moreover, we have made reasonable and feasible
future plans to further explore the functions and mechanisms of YTHDF2 in
mouse cerebral cortex neurogenesis. These findings collectively suggest that
m6A modification regulates mouse cerebral cortex neurodevelopment.
 

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