Assistan professor University of Oulu Oulu, Finland
Abstract Authors: Samina Kazi, Julio M, Castañeda, Audrey Savolainen, Yiding Xu, Ning Liu, Huanyu Qiao, Ramiro Ramirez-Solis, Kaori Nozawa, Zhifeng Yu, Martin M, Matzuk, Renata Prunskaite-Hyyryläinen
Abstract Text: MRNIP Interacts with Sex Body Chromatin to Support Meiotic Progression, Spermatogenesis, and Male Fertility in Mice
Samina Kazi1, Julio M, Castañeda2, Audrey Savolainen1, Yiding Xu3, Ning Liu3, Huanyu Qiao3, Ramiro Ramirez-Solis4, Kaori Nozawa5, Zhifeng Yu5,6, Martin M, Matzuk5,6, Renata Prunskaite-Hyyryläinen1
1Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland 2Research Institute for Microbial Diseases, Osaka University, Suita, Japan 3Department of Comparative Biosciences, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA 4University of Texas Health Science Center, San Antonio, Texas, USA 5Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas, USA 6Center for Drug Discovery, Baylor College of Medicine, Houston, Texas, USA
The MRN complex interacting protein (MRNIP) was initially identified as a protein involved in maintaining genome stability by playing a role in DNA double-strand break repair processes in mitosis. It has also been shown that MRNIP is an important factor for the protection of the replication fork during mitosis and is involved in promoting DNA double-strand break repair sensing by liquid-liquid phase separation. Our and other research works have established a central MRNIP role in male meiosis using Mrnip knock-out mouse models.
We show that Mrnip is ubiquitously expressed in multiple tissues both in mice and humans and that the gene expression in mice testes begins postnatally. Our analysis demonstrates that MRNIP is specific to male, not female meiosis. It is expressed during the first wave of spermatogenesis and becomes specific to meiocytes from mid-pachytene until the diplotene stage in prophase I. The deletion of Mrnip leads to a four-fold reduction in testes size and weight but normal body weight in mice. The histological and sperm motility analysis revealed seized spermatogenesis. Deeper studies showed that deletion of Mrnip leads to reduced sex body formation, impaired meiotic sex chromosome inactivation, and defective retroposition of X-linked genes to autosomes. Furthermore, we observed the formation of droplet-like accumulations of MRNIP that coalesce to create a distinct sub-nuclear compartment resembling nucleoli through meiotic progression. The analysis demonstrates that MRNIP droplets within the nucleus closely associate with the sex body during diplotene. Taken together, the loss of Mrnip causes meiocyte apoptosis at the diplotene stage leading to a failure in the formation of mature and motile sperm cells causing male mice infertility.
This work was supported by grants from the Academy of Finland 285151 and Profi6 336449 and the Sigrid Jusélius Foundation to R. P.-H.; Health and Bioscience doctoral program of the University of Oulu to S.K. and A.S.; the Ministry of Education, Culture, Sports, Science and Technology (MEXT)/Japan Society for the Promotion of Science (JSPS) KAKENHI grants JP18K14715 and JP20K15804 to JMC; National Institute of Health R00 HD082375 and R01 GM135549 to H.Q.; a P30 Cancer Center Support Grant (NCI-CA125123, HTAP), the Eunice Kennedy Shriver National Institute of Child Health and Human Development R01HD088412 and P01HD087157 to M.M.M., and the Bill & Melinda Gates Foundation INV-001902 to M.M.M.
