| 1. |
Sultana Tasrin, Iwamori Tokuko, Iwamori Naoki, TSNAXIP1 is required for sperm head formation and male fertility., Reproductive Medicine and Biology, 10.1002/rmb2.12520, 22, 1, e12520, 2023.06, Purpose: TRANSLIN (TSN) and its binding partner TSNAX have been reported to contribute to a wide spectrum of biological activities including spermatogenesis. TSN accompanies specific mRNA transport in male germ cells through intercellular bridges. A testis-expressed protein TSNAXIP1 was reported to interact with TSNAX. However the role of TSNAXIP1 in spermatogenesis remained unclear. This study aimed to elucidate the role of TSNAXIP1 in spermatogenesis and male fertility in mice.
Methods: TSNAXIP1 knockout (KO) mice were generated using the CRISPR-Cas9 system. The fertility, spermatogenesis, and sperm of TSNAXIP1 KO males were analyzed.
Results: TSNAXIP1, and especially its domains, are highly conserved between mouse and human. Tsnaxip1 was expressed in testis, but not in ovary. TSNAXIP1 KO mice were generated, and TSNAXIP1 KO males were found to be sub-fertile with smaller testis and lower sperm count. Although no overt abnormalities were observed during spermatogenesis, lack of TSNAXIP1 induced sperm head malformation, resulting in a unique flower-shaped sperm head. Moreover, abnormal anchorage of the sperm neck was frequently observed in TSNAXIP1 null sperm.
Conclusion: A testis-expressed gene TSNAXIP1 has important roles in sperm head morphogenesis and male fertility. Moreover, TSNAXIP1 could be a causative gene for human infertility.. |
| 2. |
Tominaga Kaoru、Sakashita Eiji、Kasashima Katsumi、Kuroiwa Kenji、Nagao Yasumitsu、Iwamori Naoki、Endo Hitoshi, Tip60/KAT5 Histone Acetyltransferase Is Required for Maintenance and Neurogenesis of Embryonic Neural Stem Cells., International Journal of Molecular Sciences, 10.3390/ijms24032113, 24, 3, 2113, 2023.01, Epigenetic regulation via epigenetic factors in collaboration with tissue-specific transcription factors is curtail for establishing functional organ systems during development. Brain development is tightly regulated by epigenetic factors, which are coordinately activated or inactivated during processes, and their dysregulation is linked to brain abnormalities and intellectual disability. However, the precise mechanism of epigenetic regulation in brain development and neurogenesis remains largely unknown. Here, we show that Tip60/KAT5 deletion in neural stem/progenitor cells (NSCs) in mice results in multiple abnormalities of brain development. Tip60-deficient embryonic brain led to microcephaly, and proliferating cells in the developing brain were reduced by Tip60 deficiency. In addition, neural differentiation and neuronal migration were severely affected in Tip60-deficient brains. Following neurogenesis in developing brains, gliogenesis started from the earlier stage of development in Tip60-deficient brains, indicating that Tip60 is involved in switching from neurogenesis to gliogenesis during brain development. It was also confirmed in vitro that poor neurosphere formation, proliferation defects, neural differentiation defects, and accelerated astrocytic differentiation in mutant NSCs are derived from Tip60-deficient embryonic brains. This study uncovers the critical role of Tip60 in brain development and NSC maintenance and function in vivo and in vitro.. |
| 3. |
Wang Y, Iwamori T, Kaneko T, Iida H, Iwamori N., Comparative distributions of RSBN1 and methylated histone H4 Lysine 20 in the mouse spermatogenesis, PLOS One, 10.1371/journal.pone.0253897, 16, 6, e0253897, 2021.06, During spermatogenesis, nuclear architecture of male germ cells is dynamically changed and epigenetic modifications, in particular methylation of histones, highly contribute to its regulation as well as differentiation of male germ cells. Although several methyltransferases and demethylases for histone H3 are involved in the regulation of spermatogenesis, roles of either histone H4 lysine 20 (H4K20) methyltransferases or H4K20 demethylases during spermatogenesis still remain to be elucidated. Recently, RSBN1 which is a testis-specific gene expressed in round spermatids was identified as a demethylase for dimethyl H4K20. In this study, therefore, we confirm the demethylase function of RSBN1 and compare distributions between RSBN1 and methylated H4K20 in the seminiferous tubules. Unlike previous report, expression analyses for RSBN1 reveal that RSBN1 is not a testis-specific gene and is expressed not only in round spermatids but also in elongated spermatids. In addition, RSBN1 can demethylate not only dimethyl H4K20 but also trimethyl H4K20 and could convert both dimethyl H4K20 and trimethyl H4K20 into monomethyl H4K20. When distribution pattern of RSBN1 in the seminiferous tubule is compared to that of methylated H4K20, both dimethyl H4K20 and trimethyl H4K20 but not monomethyl H4K20 are disappeared from RSBN1 positive germ cells, suggesting that testis-specific distribution patterns of methylated H4K20 might be constructed by RSBN1. Thus, novel expression and function of RSBN1 could be useful to comprehend epigenetic regulation during spermatogenesis.. |
| 4. |
Naoki IWAMORI, Kaoru Tominaga, Sato Tetsuya, Kevin Riehle, Tokuko Iwamori, Yasuyuki Ohkawa, Cristian Coarfa, Etsuro Ono, Martin M. Matzuk, MRG15 is required for pre-mRNA splicing and spermatogenesis, PNAS, 10.1073/pnas.1611995113, 113, 37, E5408-E5415, 2016.09, Splicing can be epigenetically regulated and involved in cellular differentiation in somatic cells, but the interplay of epigenetic factors and the splicing machinery during spermatogenesis re- mains unclear. To study these interactions in vivo, we generated a germline deletion of MORF-related gene on chromosome 15 (MRG15), a multifunctional chromatin organizer that binds to methylated histone H3 lysine 36 (H3K36) in introns of transcriptionally active genes and has been implicated in regulation of histone acetyla- tion, homology-directed DNA repair, and alternative splicing in somatic cells. Conditional KO (cKO) males lacking MRG15 in the germline are sterile secondary to spermatogenic arrest at the round spermatid stage. There were no significant alterations in meiotic division and histone acetylation. Specific mRNA sequences disappeared from 66 germ cell-expressed genes in the absence of MRG15, and specific intronic sequences were retained in mRNAs of 4 genes in the MRG15 cKO testes. In particular, introns were retained in mRNAs encoding the transition proteins that replace histones during sperm chromatin condensation. In round spermatids, MRG15 colocalizes with splicing factors PTBP1 and PTBP2 at H3K36me3 sites between the exons and single intron of transition nuclear protein 2 (Tnp2). Thus, our results reveal that MRG15 is essential for pre- mRNA splicing during spermatogenesis and that epigenetic regula- tion of pre-mRNA splicing by histone modification could be useful to understand not only spermatogenesis but also, epigenetic disor- ders underlying male infertile patients.. |
| 5. |
Dae Hwi Park, Sung Jun Hong, Ryan D. Salinas, Siyuan John Liu, Shawn W. Sun, Jacopo Sgualdino, Giuseppe Testa, Martin M. Matzuk, N. IWAMORI, Daniel A. Lim, Activation of Neuronal Gene Expression by the JMJD3 Demethylase Is Required for Postnatal and Adult Brain Neurogenesis, CELL REPORTS, 10.1016/j.celrep.2014.07.060, 8, 5, 1290-1299, 2014.09. |
| 6. |
Naoki Iwamori, Tokuko Iwamori, Martin M. Matzuk, H3K27 demethylase, JMJD3, regulates fragmentation of spermatogonial cysts., PLoS ONE, 10.1371/journal.pone.0072689, 8, 8, e72689, 2013.08. |
| 7. |
Iwamori N, Iwamori T, Matzuk MM, Characterization of spermatogonial stem cells lacking intercellular bridges and genetic replacement of a mutation in spermatogonial stem cells., PLoS One, 7, 6, e38914, 2012.06. |
| 8. |
Iwamori N, Zhao M, Meistrich ML, Matzuk MM, The testis-enriched histone demethylase, JMJD2D, regulates methylation of histone H3 lysine 9 during spermatogenesis but is dispensable for fertility. , Biol. Reprod, 84, 6, 1225-1234, 2011.06. |
