m6A修饰调控小鼠视网膜神经发育和退行性病变的机制研究

N⁶-甲基腺嘌呤 (m⁶A) 修饰是信使核糖核酸（mRNA）中最丰富的化学修饰。m⁶A甲基化转移酶和去甲基化酶动态调控m⁶A修饰水平，m⁶A阅读器蛋白识别、介导m⁶A修饰的功能。YTH结构域家族蛋白--YTHDF1、YTHDF2和YTHDF3是主要的m⁶A阅读器蛋白。传统观点认为YTHDF1调控mRNA翻译，YTHDF2促进mRNA降解，YTHDF3协同辅助YTHDF1和YTHDF2的功能；然而最新的观点则认为YTHDF1/2/3冗余地调控mRNA稳定性从而影响生理功能。研究表明m⁶A修饰可以调节大脑皮层和小脑等区域的神经发育过程，但以视网膜为模型，对m⁶A修饰在神经元产生和视觉神经环路形成中的功能研究仍然有待进行。视网膜神经节细胞作为视网膜中唯一能够将神经信号传递到大脑的神经元类型，其树突发育对于接收和整合视觉信号极为重要。此外，视网膜神经节细胞的退行性病变和死亡也是青光眼疾病发生中的重要表征，同时其树突衰退与青光眼的疾病发生也有着密切联系，因此探究m⁶A修饰在视网膜神经节细胞树突发育乃至青光眼疾病发生过程的影响同样尤为重要。

本研究采用Six3-cre在视网膜中条件性敲除的m⁶A甲基转移酶基因Mettl14，通过组织切片与免疫荧光分析了Mettl14缺失后视网膜神经元产生的变化。实验结果表明：缺失Mettl14会导致视网膜前体细胞增殖后延，无长突细胞和双极细胞等后期神经元的产生受阻，以及视网膜片层化结构紊乱等视网膜发育异常。此外，m⁶A阅读器蛋白Ythdf1/2/3的单独缺失和Ythdf1/2双重敲除均不影响视网膜神经元产生过程，只有Ythdf1/2/3三重敲除的小鼠视网膜才能重现Mettl14敲除后神经元产生的发育异常。小鼠视网膜YTHDF1和YTHDF2 RIP-seq基因功能注释分析结果表明YTHDF1和YTHDF2共同调控一批与神经元产生相关的靶mRNAs，进一步证明了YTHDF1/2/3在调控视网膜神经元产生过程中具有冗余性。

针对YTHDF2在视网膜神经节细胞中的高表达，本研究继续探索了YTHDF2在视网膜神经节细胞树突发育过程中的作用。通过体外原代培养的视网膜细胞和Ythdf2 条件性敲除小鼠视网膜铺片，证明了YTHDF2缺失会导致视网膜神经节细胞的树突分支明显增加。通过组织切片分析和视动反应行为学实验，发现Ythdf2条件性敲除会导致视网膜内丛状层变厚并产生更多的突触，并且能够轻微提升小鼠视动反应的能力。结合YTHDF2 RIP-seq和Ythdf2敲低后蛋白质组质谱的结果，本研究鉴定了YTHDF2的靶mRNAs--Kalrn、Strn和Ubr4；证明了YTHDF2能够识别与结合这些m⁶A修饰的mRNAs，促进靶mRNAs的降解进而影响蛋白表达水平。研究在体外条件下明确了Kalrn、Strn和Ubr4能够调控视网膜神经节细胞树突发育，还通过体外培养和玻璃体腔AAV感染等实验，证明了干扰YTHDF2靶mRNAs的表达能够有效地拯救YTHDF2缺失引起的视网膜神经节细胞树突分支增加的现象。

本研究最后利用急性高眼压这一青光眼病理模型，分析了YTHDF2及其靶mRNAs在青光眼疾病发生中的功能和机制。研究发现YTHDF2在急性高眼压模型中表达量上升，条件性敲除Ythdf2能够有效缓解急性高眼压导致的视网膜神经节细胞的树突衰退和细胞凋亡。本研究还鉴定了YTHDF2在青光眼模型中的另一组靶mRNAs--Hapa12a和Islr2，其表达水平在急性高眼压模型中下降；AAV过表达Hapa12a和Islr2则能够增强视网膜神经节细胞对急性高眼压诱发的病理性变性的抵御能力。

本研究发现了m⁶A修饰可以调控视网膜神经元产生，证实了m⁶A阅读器蛋白YTHDF1/2/3在介导m⁶A修饰调控神经元产生中存在冗余性。这些结果有助于更好地理解m⁶A阅读器蛋白作用的分子协助机制，对理解不同的m⁶A阅读器蛋白在神经元产生中的功能关系也有着重要意义。此外，本研究还阐明了YTHDF2参与调控视网膜神经节细胞树突发育和青光眼疾病发生的分子机制，证明了YTHDF2与m⁶A修饰能够介导调节视网膜神经节细胞树突发育和维持过程，YTHDF2及其靶mRNAs在青光眼疾病发生中的功能对于开发新的治疗手段也很有价值。

N⁶-methyladenosine (m⁶A) modification, as the most abundant chemical modification on mRNA, is dynamically regulated by its "writers" and "erasers", and recognized by its "readers". The YTH domain family proteins are the most important m⁶A readers. In the traditional theory, YTHDF1 regulates mRNA translation, YTHDF2 enhances mRNA degradation, and YTHDF3 acts as the helper proteins cooperating with YTHDF1 and YTHDF2. However, some initial studies have suggested that YTHDF1/2/3 functions redundantly to regulate mRNA stability and functions. Recent studies have shown that m⁶A modification regulates neurogenesis in the cortex and cerebellum, but how m⁶A modification regulates retinal neurogenesis and neural circuit formation is still unknown. Retinal ganglion cells (RGCs) are the last and only output neurons of the vertebrate retina and their dendrites collect and integrate electrical information concerning the visual signal from all the other cells preceding them. Furthermore, death of RGCs is a feature of glaucoma processes and degeneration of RGC dendrites is closely related to glaucoma processes. Exploring the function of m⁶A modification in RGC dendrite development and even glaucoma processes is of great importance.

In this study, the m⁶A writer Mettl14 was conditionally knocked out by Six3-cre in the retina, and immunostaining of tissue sections was applied to identify differences in retinal neurogenesis after METTL14 depletion. It reveals that deletion of METTL14 leads to severely impaired retinal neurogenesis, including delayed proliferation of retinal progenitors, decreased generation of late-born neurons amacrine cells and bipolar cells, and deformed retinal patterning. Single deletion of Ythdf1/2/3 or double deletion of Ythdf1/2 did not affect retinal neurogenesis. Only triple knockout of Ythdf1/2/3 recapitulated defects in retinal neurogenesis caused by conditional knockout of Mettl14 in the retina. Gene ontology of genes identified by anti-YTHDF1 and anti-YTHDF2 RNA immunoprecipitation followed by RNA sequencing of elutes (RIP-seq) demonstrated that YTHDF1 and YTHDF2 share a large pool of target mRNAs related to neurogenesis in the mouse retina, supporting their redundant functions in mediating m⁶A regulation of retinal neurogenesis.

This study discovered the function of YTHDFs in the development of RGC dendrites. Results of primary cultured RGCs and retinal Ythdf2 cKO immunofluorescence (IF) showed that loss of YTHDF2 increased branching of RGC dendrites. Using tissue analysis and optomotor testing, it was elucidated that deletion of Ythdf2 increased synapses in the inner plexiform layer and slightly improved visual ability in mice. By anti-YTHDF2 RIP-seq and protein mass spectrometry after Ythdf2 knockdown, we identified Kalrn, Strn and Ubr4 as target genes of YTHDF2, revealed that YTHDF2 binds to these m⁶A-tagged mRNAs and enhances mRNA degradation to regulate mRNA and protein expression levels. Silencing YTHDF2 target genes--Kalrn, Strn, and Ubr4 decreased RGC dendrite branching. Rescue of Ythdf2 cKO increased RGC dendrite branching by silencing YTHDF2 target genes was achieved in cultured RGCs in vitro and AAV infection in vivo.

Finally, the functions of YTHDF2 and its target genes in glaucomatous processes were identified by an acute glaucoma model caused by acute ocular hypertension (AOH). YTHDF2 expression level was increased after AOH. Knockout of Ythdf2 protected the retina from RGC dendrite degeneration and soma loss caused by AOH. Hspa12a and Islr2, as YTHDF2 target genes, were down-regulated after AOH. Overexpression of Hspa12a and Islr2 by AAV had neuroprotective roles on RGC degeneration in the glaucomatous retina.

This study confirms that the regulation of m⁶A modification in retinal neurogenesis is redundantly mediated by m⁶A reader proteins YTHDF1/2/3. It is helpful to understand the molecular mechanism of m⁶A reader proteins and how different m⁶A reader proteins mediate the regulation of m⁶A modification in neurogenesis. Furthermore, this study sheds light on the molecular mechanism of YTHDF2 in regulating RGC dendrite development and glaucomatous progress. It firstly reveals the perspective that YTHDF2 and m⁶A modification could regulate the development and maintenance of RGC dendrites. Functions of YTHDF2 and its target mRNAs in glaucomatous processes might also be valuable in developing new treatment approaches.

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