Adenosine methylation of messenger RNA at the N6 position (m6A) is a non-editing modification that can affect several aspects of mRNA metabolism. Dm Ime4, also known as METTL3, MTA, and MTA-70 in other organisms, is the catalytic subunit of the methyltransferase complex that adds this modification. Dm ime4 is evolutionarily conserved and essential for development in metazoans and plants. Because of its pleiotropic effects, it has been difficult to establish the main reason why embryonic arrest occurs in plants, mice, and zebrafish. Using a strategy that depletes Dm Ime4 specifically in the somatic cyst cells of Drosophila testes without affecting essential functions in development, our lab has found that Dm Ime4 may potentially regulate splicing of profilin (chic) mRNA, the message for an essential and evolutionarily conserved protein mainly known for its function in actin polymerization. One of the lesser known roles for Chic is its requirement for establishment and maintenance of the somatic cyst-cell permeability barrier in Drosophila spermatogenesis. Chic and Dm Ime4 colocalize and are abundant in somatic cyst cells throughout spermatogenesis. Upon selective depletion of Dm Ime4, we observe significant reduction of Chic protein levels and malfunction of the permeability barrier. We have found that chic mRNA contains intronic Dm Ime4 binding sites that can form the hairpin structures required for recognition by the methyltransferase complex. Our data show that the reduced levels of Chic protein observed in Dm ime4 somatic cyst-cell knockdowns could be the result of aberrant splicing of its mRNA. In turn, low levels of Chic are known to affect the function of the somatic permeability barrier, leading to germline death and the reduced fertility observed in Dm ime4 knockdown males. We propose that Dm Ime4 may regulate chic in other developmental contexts and in other organisms, including mice and humans. Chic is an essential protein that is evolutionarily conserved, and establishment and maintenance of cell barriers and domains are important strategies used in metazoan development. Taken together, our findings define a framework to investigate specific functions of Dm Ime4 and its homologs in multicellular organisms by bypassing its pleiotropic requirement in early developmental stages.

中文翻译：

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Dm Ime4 耗竭影响果蝇精子发生的通透性屏障和别致功能

N6 位置 (m6A) 信使 RNA 的腺苷甲基化是一种非编辑修饰，可影响 mRNA 代谢的多个方面。Dm Ime4，在其他生物中也称为 METTL3、MTA 和 MTA-70，是添加这种修饰的甲基转移酶复合物的催化亚基。Dm ime4 在进化上是保守的，对后生动物和植物的发育至关重要。由于其多效性，很难确定植物、小鼠和斑马鱼发生胚胎停滞的主要原因。我们的实验室使用一种在果蝇睾丸的体细胞囊肿细胞中专门消耗 Dm Ime4 而不影响发育中的基本功能的策略，发现 Dm Ime4 可能潜在地调节 profilin (chic) mRNA 的剪接，一种重要且进化上保守的蛋白质的信息，主要以其在肌动蛋白聚合中的功能而闻名。Chic 鲜为人知的作用之一是它需要在果蝇精子发生中建立和维持体细胞囊肿细胞通透性屏障。Chic 和 Dm Ime4 共定位并在整个精子发生过程中大量存在于体细胞囊肿细胞中。在选择性消耗 Dm Ime4 后，我们观察到 Chic 蛋白水平显着降低和渗透屏障功能障碍。我们发现chic mRNA 包含内含子Dm Ime4 结合位点，可以形成甲基转移酶复合物识别所需的发夹结构。我们的数据显示，在 Dm ime4 体细胞囊肿细胞敲低中观察到的 Chic 蛋白水平降低可能是其 mRNA 异常剪接的结果。反过来，已知低水平的 Chic 会影响体细胞渗透屏障的功能，导致种系死亡和在 Dm ime4 敲除雄性中观察到的生育力降低。我们建议 Dm Ime4 可能在其他发育环境和其他生物体（包括小鼠和人类）中调节别致。Chic 是一种进化上保守的必需蛋白质，细胞屏障和结构域的建立和维持是后生动物发育中使用的重要策略。总之，我们的研究结果定义了一个框架，通过绕过早期发育阶段的多效性需求来研究 Dm Ime4 及其同系物在多细胞生物中的特定功能。导致种系死亡和在 Dm ime4 敲除雄性中观察到的生育力降低。我们建议 Dm Ime4 可能在其他发育环境和其他生物体（包括小鼠和人类）中调节别致。Chic 是一种进化上保守的必需蛋白质，细胞屏障和结构域的建立和维持是后生动物发育中使用的重要策略。总之，我们的研究结果定义了一个框架，通过绕过早期发育阶段的多效性需求来研究 Dm Ime4 及其同系物在多细胞生物中的特定功能。导致种系死亡和在 Dm ime4 敲除雄性中观察到的生育力降低。我们建议 Dm Ime4 可能在其他发育环境和其他生物体（包括小鼠和人类）中调节别致。Chic 是一种进化上保守的必需蛋白质，细胞屏障和结构域的建立和维持是后生动物发育中使用的重要策略。总之，我们的研究结果定义了一个框架，通过绕过早期发育阶段的多效性需求来研究 Dm Ime4 及其同系物在多细胞生物中的特定功能。细胞屏障和区域的建立和维持是后生动物发育中使用的重要策略。总之，我们的研究结果定义了一个框架，通过绕过早期发育阶段的多效性要求来研究 Dm Ime4 及其同系物在多细胞生物中的特定功能。细胞屏障和区域的建立和维持是后生动物发育中使用的重要策略。总之，我们的研究结果定义了一个框架，通过绕过早期发育阶段的多效性需求来研究 Dm Ime4 及其同系物在多细胞生物中的特定功能。