Padma Radhika, Subramanian Manivannan, Chimata Anuradha Venkatakrishnan, Rai Arushi, Yogi Sunanda, Sangeeth Anjali, Kango-Singh Madhuri, Singh Amit
Department of Biology, University of Dayton, Dayton, OH 45469, USA.
Premedical Program, University of Dayton, Dayton, OH 45469, USA.
Development. 2025 Jul 15;152(14). doi: 10.1242/dev.204373. Epub 2025 Jul 16.
During development, regulation of gene expression is key to cellular homeostasis. Gene expression regulation by non-coding RNAs involves the prevention of mRNA accumulation or the inhibition of translation of their target gene. In a forward-genetic screen to identify the microRNA involved in the growth and patterning of the Drosophila eye, we identified the highly conserved miR-137. Gain of function of miR-137 results in a reduced-eye phenotype by downregulating retinal determination and differentiation markers, and by upregulating negative regulators of eye development, such as Wingless (Wg) and Homothorax (Hth). Loss of function of miR-137 results in an enlarged-eye phenotype. Using bioinformatics and genetic approaches, we identified the oncogene Myc as the target of miR-137. Gain of function of Myc can rescue the reduced-eye phenotype of miR-137 gain of function, and vice versa. We tested the role of miR-137 in regulating Myc levels in the RasV12;scribRNAi, a tumor model of oncogenic cooperation that results in neoplastic tumors. Gain of function of miR-137 in the RasV12;scribRNAi background significantly reduced tumor phenotype as well as Myc levels in the eye. Our studies highlight miR-137 as a post-transcriptional regulator of Myc and a promising therapeutic target for diseases associated with Myc accumulation.
在发育过程中，基因表达的调控是细胞内稳态的关键。非编码RNA对基因表达的调控涉及阻止mRNA积累或抑制其靶基因的翻译。在一项旨在鉴定参与果蝇眼睛生长和模式形成的 microRNA 的正向遗传学筛选中，我们鉴定出了高度保守的 miR-137。miR-137 的功能获得通过下调视网膜决定和分化标志物以及上调眼睛发育的负调节因子，如无翅基因（Wg）和同源胸节基因（Hth），导致眼睛变小的表型。miR-137 的功能缺失则导致眼睛变大的表型。通过生物信息学和遗传学方法，我们确定原癌基因 Myc 是 miR-137 的靶标。Myc 的功能获得可以挽救 miR-137 功能获得导致的眼睛变小表型，反之亦然。我们在 RasV12;scribRNAi（一种导致肿瘤形成的致癌协同作用肿瘤模型）中测试了 miR-137 在调节 Myc 水平方面的作用。在 RasV12;scribRNAi 背景下 miR-137 的功能获得显著降低了肿瘤表型以及眼睛中的 Myc 水平。我们的研究突出了 miR-137 作为 Myc 的转录后调节因子以及与 Myc 积累相关疾病的有前景的治疗靶点。
