MEGF9, a novel transmembrane protein with multiple EGF-like repeats, is predominantly expressed in the developing and adult central and peripheral nervous systems. It consists of an N-terminal region with potential O-glycosylation sites, five EGF-like domains homologous to laminins' short arms, a single-pass transmembrane domain, and a conserved intracellular domain with potential phosphorylation sites. It may function as a guidance or signalling molecule and is developmentally regulated [4].

In lipopolysaccharide (LPS)-induced cardiac dysfunction, MEGF9 expressions were reduced in cardiomyocytes, mice, and septic patients, and negatively correlated with cardiac dysfunction. MEGF9 overexpression attenuated, while knockdown aggravated LPS-induced inflammation and oxidative damage in vivo and in vitro, regulating cardiac injury. It alleviated LPS-induced cardiac dysfunction through activating the AMPK pathway [1]. In osteoarthritis, MEGF9 was a predicted target of miR-7. Upregulation of miR-7 or MEGF9 increased the expression of EGFR, MMP-13, and ADAMTS-5, aggravating cartilage degradation via activation of the PI3K/AKT/mTOR signalling pathway [2]. Mendelian randomization analysis showed MEGF9 was positively associated with male infertility in varicocele. Its expression increased in the varicocele model group and decreased after treatment with Bu Shen Huo Xue Prescription (BSHXP), suggesting BSHXP inhibiting MEGF9 may be a potential therapeutic target [3]. In neuropathic pain, MEGF9 was one of the candidate genes associated with microglial polarization, with higher expression in the NP model group compared to the sham group. In breast cancer, miR-125b, which was decreased in expression, performed its tumor-suppressor function via directly targeting MEGF9 [6]. In adolescent major depressive disorder, MEGF9 was identified as a hub gene in a module associated with stress, inflammation, and immune responses.

In summary, MEGF9 plays crucial roles in various biological processes and disease conditions. Studies, including those using in vivo models like LPS-treated mice, have revealed its significance in cardiac function, osteoarthritis, male infertility, neuropathic pain, breast cancer, and adolescent depression. These findings provide insights into potential therapeutic targets for these diseases.

References:

1. Jin, Zhili, Li, Xianqing, Liu, Huixia, Fan, Di, Wang, Hairong. 2024. MEGF9 prevents lipopolysaccharide-induced cardiac dysfunction through activating AMPK pathway. In Redox report : communications in free radical research, 30, 2435252. doi:10.1080/13510002.2024.2435252. https://pubmed.ncbi.nlm.nih.gov/39737911/

2. Jiang, Lifeng, Zhou, Xindie, Xu, Kai, Zhu, Junfeng, Wu, Lidong. . miR-7/EGFR/MEGF9 axis regulates cartilage degradation in osteoarthritis via PI3K/AKT/mTOR signaling pathway. In Bioengineered, 12, 8622-8634. doi:10.1080/21655979.2021.1988362. https://pubmed.ncbi.nlm.nih.gov/34629037/

3. Cai, Bin, Sun, Dalin, Deng, Weimin, Liu, Yuanyuan, Jin, Baofang. 2024. Mendelian randomization analysis and validation supports MEGF9 and MLLT11 as potential targets for the treatment of varicocele and male infertility. In Frontiers in endocrinology, 15, 1416384. doi:10.3389/fendo.2024.1416384. https://pubmed.ncbi.nlm.nih.gov/39391881/

4. Brandt-Bohne, Ulrike, Keene, Douglas R, White, Fletcher A, Koch, Manuel. . MEGF9: a novel transmembrane protein with a strong and developmentally regulated expression in the nervous system. In The Biochemical journal, 401, 447-57. doi:. https://pubmed.ncbi.nlm.nih.gov/16981854/

5. Gao, Sheng, Sun, Yuyan, Jia, Shu, Meng, Chunyang. 2024. Transcriptome analysis unveils PLSCR1 associated with microglial polarization in neuropathic pain. In Gene, 933, 148961. doi:10.1016/j.gene.2024.148961. https://pubmed.ncbi.nlm.nih.gov/39312982/

6. Feliciano, Andrea, Castellvi, Josep, Artero-Castro, Ana, Ramón Y Cajal, Santiago, Lleonart, Matilde E. 2013. miR-125b acts as a tumor suppressor in breast tumorigenesis via its novel direct targets ENPEP, CK2-α, CCNJ, and MEGF9. In PloS one, 8, e76247. doi:10.1371/journal.pone.0076247. https://pubmed.ncbi.nlm.nih.gov/24098452/

7. Zhao, Bao, Fan, Qingyue, Liu, Jintong, Wang, Pingping, Zhang, Wenxin. 2022. Identification of Key Modules and Genes Associated with Major Depressive Disorder in Adolescents. In Genes, 13, . doi:10.3390/genes13030464. https://pubmed.ncbi.nlm.nih.gov/35328018/