Fmn2, a member of the formin family, is crucial for multiple biological processes. It plays a key role in brain morphogenesis by regulating growth cone motility. It functions as a clutch molecule, mediating the coupling of the actin cytoskeleton to the growth substrate via point contact adhesion complexes, thereby generating traction forces for growth cone translocation [1]. Fmn2 also has a role in cell cycle regulation as it can promote cell cycle arrest by inhibiting p21 degradation [5].

In neural development, Fmn2 is implicated in axon collateral branching. It localizes to axonal F-actin patches, regulating their lifetime and size, and protects these patches from disassembly by ADF, thus facilitating the initiation of axonal protrusions that lead to collateral branch formation [3]. In addition, it couples dynamic microtubules to F-actin, which is essential for growth cone chemotaxis [7]. In ovarian function, heterozygous FMN2 missense variants are associated with premature ovarian insufficiency, indicating its role in ovarian reserve [2]. In cancer, exosomal circ_FMN2 derived from colorectal cancer patients' serum promotes cancer progression through the miR-338-3p/MSI1 axis [4]. Also, FMN2 is upregulated in human melanomas, and its disruption in mouse melanoma cells inhibits extravasation and metastasis to the lung by protecting the nucleus during confined migration [6].

In summary, Fmn2 is essential for neural development, cell cycle regulation, ovarian function, and has implications in cancer metastasis. Studies using various models, including those in mice, have revealed its role in these biological processes and disease conditions, highlighting its significance as a potential therapeutic target in related diseases.

References:

1. Ghate, Ketakee, Mutalik, Sampada P, Sthanam, Lakshmi Kavitha, Sen, Shamik, Ghose, Aurnab. 2020. Fmn2 Regulates Growth Cone Motility by Mediating a Molecular Clutch to Generate Traction Forces. In Neuroscience, 448, 160-171. doi:10.1016/j.neuroscience.2020.09.046. https://pubmed.ncbi.nlm.nih.gov/33002558/

2. Li, Jie, Peng, Tianliu, Wang, Le, Xiao, Hongmei, Shi, Xiaobo. 2022. Heterozygous FMN2 missense variant found in a family case of premature ovarian insufficiency. In Journal of ovarian research, 15, 31. doi:10.1186/s13048-022-00960-y. https://pubmed.ncbi.nlm.nih.gov/35227295/

3. Kundu, Tanushree, Siva Das, Sooraj, Sewatkar, Lisas K, Nagar, Dhriti, Ghose, Aurnab. 2022. Antagonistic Activities of Fmn2 and ADF Regulate Axonal F-Actin Patch Dynamics and the Initiation of Collateral Branching. In The Journal of neuroscience : the official journal of the Society for Neuroscience, 42, 7355-7369. doi:10.1523/JNEUROSCI.3107-20.2022. https://pubmed.ncbi.nlm.nih.gov/36481742/

4. Yu, Qiyao, Zhang, Yi, Tian, Yanming, Ju, Yingchao, Gao, Chao. 2023. Exosomal Circ_FMN2 Derived from the Serum of Colorectal Cancer Patients Promotes Cancer Progression by miR-338-3p/MSI1 Axis. In Applied biochemistry and biotechnology, 195, 7322-7337. doi:10.1007/s12010-023-04456-3. https://pubmed.ncbi.nlm.nih.gov/36995659/

5. Yamada, Kayo, Ono, Motoharu, Bensaddek, Dalila, Lamond, Angus I, Rocha, Sonia. 2013. FMN2 is a novel regulator of the cyclin-dependent kinase inhibitor p21. In Cell cycle (Georgetown, Tex.), 12, 2348-54. doi:10.4161/cc.25511. https://pubmed.ncbi.nlm.nih.gov/23839046/

6. Skau, Colleen T, Fischer, Robert S, Gurel, Pinar, Steeg, Patricia S, Waterman, Clare M. 2016. FMN2 Makes Perinuclear Actin to Protect Nuclei during Confined Migration and Promote Metastasis. In Cell, 167, 1571-1585.e18. doi:10.1016/j.cell.2016.10.023. https://pubmed.ncbi.nlm.nih.gov/27839864/

7. Kundu, Tanushree, Dutta, Priyanka, Nagar, Dhriti, Maiti, Sankar, Ghose, Aurnab. 2021. Coupling of dynamic microtubules to F-actin by Fmn2 regulates chemotaxis of neuronal growth cones. In Journal of cell science, 134, . doi:10.1242/jcs.252916. https://pubmed.ncbi.nlm.nih.gov/34313311/