Ddx25, also known as Gonadotropin-regulated testicular RNA helicase (GRTH), is a DEAD-box RNA helicase. It is a key post-transcriptional regulator essential for spermatogenesis, being involved in the transport of target mRNAs to the cytoplasm and regulation of their translation [2,3,5]. It is expressed in germ cells (meiotic spermatocytes and round spermatids) and Leydig cells, and plays a central role in preventing germ cell apoptosis [5]. Mouse models have been crucial for studying its function.

Male mice lacking GRTH (GRTH-KO) are sterile due to spermatogenic arrest at step 8 of spermiogenesis, as round spermatids fail to elongate [4,5,6]. GRTH-KO and GRTH Knock-In (KI) mice with R242H mutation (lacking pGRTH) show spermatogenic arrest, revealing the importance of phosphorylated GRTH in spermatid development, chromatin compaction, and remodeling through miRNA-mRNA interactions [4,6]. In humans, mutations in Ddx25 may be associated with non-obstructive azoospermia, and genetic diagnosis could help predict the success of sperm retrieval [1].

In conclusion, Ddx25 is an essential regulator of spermatogenesis. Mouse models, especially GRTH-KO and KI models, have significantly contributed to understanding its role in spermatid development and the disease context of male infertility, providing insights for potential male contraceptive development and genetic diagnosis of non-obstructive azoospermia.

References:

1. Kherraf, Zine-Eddine, Cazin, Caroline, Bouker, Amine, Arnoult, Christophe, Ray, Pierre F. 2022. Whole-exome sequencing improves the diagnosis and care of men with non-obstructive azoospermia. In American journal of human genetics, 109, 508-517. doi:10.1016/j.ajhg.2022.01.011. https://pubmed.ncbi.nlm.nih.gov/35172124/

2. Raju, Murugananthkumar, Kavarthapu, Raghuveer, Anbazhagan, Rajakumar, Hassan, Sergio A, Dufau, Maria L. 2021. Blockade of GRTH/DDX25 Phosphorylation by Cyclic Peptides Provides an Avenue for Developing a Nonhormonal Male Contraceptive. In Journal of medicinal chemistry, 64, 14715-14727. doi:10.1021/acs.jmedchem.1c01201. https://pubmed.ncbi.nlm.nih.gov/34601876/

3. Dufau, Maria L, Tsai-Morris, Chon-Hwa. 2007. Gonadotropin-regulated testicular helicase (GRTH/DDX25): an essential regulator of spermatogenesis. In Trends in endocrinology and metabolism: TEM, 18, 314-20. doi:. https://pubmed.ncbi.nlm.nih.gov/17889551/

4. Anbazhagan, Rajakumar, Kavarthapu, Raghuveer, Dale, Ryan, Faucz, Fabio R, Dufau, Maria L. 2023. miRNA Expression Profiles of Mouse Round Spermatids in GRTH/DDX25-Mediated Spermiogenesis: mRNA-miRNA Network Analysis. In Cells, 12, . doi:10.3390/cells12050756. https://pubmed.ncbi.nlm.nih.gov/36899892/

5. Tsai-Morris, Chon-Hwa, Sheng, Yi, Gutti, Ravi K, Tang, Pei-Zhong, Dufau, Maria L. 2009. Gonadotropin-regulated testicular RNA helicase (GRTH/DDX25): a multifunctional protein essential for spermatogenesis. In Journal of andrology, 31, 45-52. doi:10.2164/jandrol.109.008219. https://pubmed.ncbi.nlm.nih.gov/19875492/

6. Kavarthapu, Raghuveer, Anbazhagan, Rajakumar, Raju, Murugananthkumar, Pickel, James, Dufau, Maria L. . Targeted knock-in mice with a human mutation in GRTH/DDX25 reveals the essential role of phosphorylated GRTH in spermatid development during spermatogenesis. In Human molecular genetics, 28, 2561-2572. doi:10.1093/hmg/ddz079. https://pubmed.ncbi.nlm.nih.gov/31009948/