Ythdc2, a member of the YT521-B homology (YTH) gene family, is an N6-methyladenosine (m6A) binding protein and RNA helicase. It is involved in RNA metabolism, regulating processes like translation efficiency and mRNA abundance. It plays a crucial role in mammalian spermatogenesis and is associated with multiple biological processes and disease-related pathways [2,3,5]. Genetic models, such as knockout (KO) and conditional knockout (CKO) mouse models, are valuable tools for studying Ythdc2's functions.

Ythdc2 knockout mice are infertile, with males having smaller testes and females having smaller ovaries. Germ cells in these KO mice do not progress past the zygotene stage, indicating its essential role in spermatogenesis [2]. Conditional knockout of Ythdc2 in late spermatocytes after meiotic prophase initiation allows cells to reach the pachytene stage but they fail to transition to the diplotene stage, suggesting Ythdc2 has a late-stage role in meiotic progression [3]. In breast cancer, knockdown of Ythdc2 in four different subtype cell lines attenuates sphere-forming and metastatic abilities, with stemness and EMT markers downregulated, highlighting its role in breast cancer tumorigenesis and metastasis [1]. In colorectal cancer, downregulation of Ythdc2 increases the stability and expression of LIMK1 mRNA, leading to 5-FU chemoresistance [4].

In summary, Ythdc2 is essential for spermatogenesis and meiotic progression in germ cells. Model-based research, especially KO and CKO mouse models, has also revealed its significance in diseases like breast cancer and colorectal cancer. Understanding Ythdc2's functions provides insights into reproductive biology and cancer mechanisms, potentially guiding new therapeutic strategies.

References:

1. Tanabe, Atsushi, Nakayama, Takatoshi, Kashiyanagi, Jo, Takemasa, Ichiro, Sahara, Hiroeki. 2022. YTHDC2 Promotes Malignant Phenotypes of Breast Cancer Cells. In Journal of oncology, 2022, 9188920. doi:10.1155/2022/9188920. https://pubmed.ncbi.nlm.nih.gov/36245989/

2. Hsu, Phillip J, Zhu, Yunfei, Ma, Honghui, Shen, Bin, He, Chuan. 2017. Ythdc2 is an N6-methyladenosine binding protein that regulates mammalian spermatogenesis. In Cell research, 27, 1115-1127. doi:10.1038/cr.2017.99. https://pubmed.ncbi.nlm.nih.gov/28809393/

3. Bailey, Alexis S, Fuller, Margaret T. 2024. YTHDC2 serves a distinct late role in spermatocytes during germ cell differentiation. In Proceedings of the National Academy of Sciences of the United States of America, 121, e2309548121. doi:10.1073/pnas.2309548121. https://pubmed.ncbi.nlm.nih.gov/39378093/

4. Chen, Lu, Sun, Kangyue, Qin, Wenjie, Liu, Side, Zhang, Yue. 2023. LIMK1 m6A-RNA methylation recognized by YTHDC2 induces 5-FU chemoresistance in colorectal cancer via endoplasmic reticulum stress and stress granule formation. In Cancer letters, 576, 216420. doi:10.1016/j.canlet.2023.216420. https://pubmed.ncbi.nlm.nih.gov/37778684/

5. Saito, Yuhki, Hawley, Ben R, Puno, M Rhyan, Keeney, Scott, Jain, Devanshi. 2022. YTHDC2 control of gametogenesis requires helicase activity but not m6A binding. In Genes & development, 36, 180-194. doi:10.1101/gad.349190.121. https://pubmed.ncbi.nlm.nih.gov/35058317/