| 1. |
Takashi Baba, Junsei Mimura, Naohito Nakamura, Nobuhiro Harada, Masayuki Yamamoto, Ken-Ichirou Morohashi, Yoshiaki Fujii-Kuriyama, Intrinsic function of the aryl hydrocarbon (dioxin) receptor as a key factor in female reproduction., Molecular and cellular biology, 25, 22, 10040-51, 2005.11, Dioxins exert a variety of adverse effects on organisms, including teratogenesis, immunosuppression, tumor promotion, and estrogenic action. Studies using aryl hydrocarbon receptor (AhR)-deficient mice suggest that the majority of these toxic effects are mediated by the AhR. In spite of the adverse effects mediated by this receptor, the AhR gene is conserved among a number of animal species, ranging from invertebrates to vertebrates. This high degree of conservation strongly suggests that AhR possesses an important physiologic function, and a critical function is also supported by the reduced fertility observed with AhR-null female mice. We demonstrate that AhR plays a crucial role in female reproduction by regulating the expression of ovarian P450 aromatase (Cyp19), a key enzyme in estrogen synthesis. As revealed by in vitro reporter gene assay and in vivo chromatin immunoprecipitation assay, AhR cooperates with an orphan nuclear receptor, Ad4BP/SF-1, to activate Cyp19 gene transcription in ovarian granulosa cells. Administration to female mice of an AhR ligand, DMBA (9,10-dimethyl-1,2-benzanthracene), induced ovarian Cyp19 gene expression, irrespective of the intrinsic phase of the estrus cycle. In addition to elucidating a physiological function for AhR, our studies also suggest a possible mechanism for the toxic effects of exogenous AhR ligands as endocrine disruptors.. |
| 2. |
Takashi Baba, Hiroyuki Otake, Tetsuya Sato, Kanako Miyabayashi, Yurina Shishido, Chia-Yih Wang, Yuichi Shima, Hiroshi Kimura, Mikako Yagi, Yasuhiro Ishihara, Shinjiro Hino, Hidesato Ogawa, Mitsuyoshi Nakao, Takeshi Yamazaki, Dongchon Kang, Yasuyuki Ohkawa, Mikita Suyama, Bon-Chu Chung, Ken-Ichirou Morohashi, Glycolytic genes are targets of the nuclear receptor Ad4BP/SF-1, Nature Communications, 10.1038/ncomms4634, 5, 3634-3634, 2014.04, Genetic deficiencies in transcription factors can lead to the loss of certain types of cells and tissue. The steroidogenic tissue-specific nuclear receptor Ad4BP/SF-1 (NR5A1) is one such gene, because mice in which this gene is disrupted fail to develop the adrenal gland and gonads. However, the specific role of Ad4BP/SF-1 in these biological events remains unclear. Here we use chromatin immunoprecipitation sequencing to show that nearly all genes in the glycolytic pathway are regulated by Ad4BP/SF-1. Suppression of Ad4BP/SF-1 by small interfering RNA reduces production of the energy carriers ATP and nicotinamide adenine dinucleotide phosphate, as well as lowers expression of genes involved in glucose metabolism. Together, these observations may explain tissue dysgenesis as a result of Ad4BP/SF-1 gene disruption in vivo. Considering the function of estrogen-related receptor a, the present study raises the possibility that certain types of nuclear receptors regulate sets of genes involved in metabolic pathways to generate energy carriers.. |
| 3. |
Yanai S, Baba T, Inui K, Miyabayashi K, Han S, Inoue M, Takahashi F, Kanai Y, Ohkawa Y, Choi MH, Morohashi KI., Gene expression and functional abnormalities in XX/Sry Leydig cells, SCIENTIFIC REPORTS, 10.1038/s41598-020-80741-z, 11, 1, 2021.01. |
| 4. |
Soyun Han, Takashi Baba, Shogo Yanai, Dong Jun Byun, Ken-Ichirou Morohashi, Jae-Hong Kim, Man Ho Choi , GC-MS-based metabolic signatures reveal comparative steroidogenic pathways between fetal and adult mouse testes., Andrology, 10.1111/andr.12893., PMID: 32810374, 2020.08, Background: Previous studies on gonadal steroidogenesis have not compared metabolic pathways between fetal and adult mouse testes to date.
Objectives: To evaluate comparative metabolic signatures of testicular steroids between fetus and adult mice using gas chromatography-mass spectrometry (GC-MS)-based steroid profiling.
Materials and methods: GC-MS with molecular-specific scan modes was optimized for selective and sensitive detection of 23 androgens, 7 estrogens, 14 progestogens, and 13 corticoids from mouse testes with a quantification limit of 0.1-5.0 ng/mL and reproducibility (coefficient of variation: 0.3%-19.9%). Based on 26 steroids quantitatively detected in testes, comparative steroid signatures were analyzed for mouse testes of 8 fetuses on embryonic day 16.5 and 8 adults on postnatal days 56-60.
Results: In contrast to large amounts of steroids in adult testes (P < .0002), all testicular levels per weight unit of protein were significantly increased in fetal testes (P < .002, except 6β-hydroxytestosterone of P = .065). Both 11β-hydroxyandrostenedione and 7α-hydroxytestosterone were only measurable in fetal testes, and metabolic ratios of testosterone to androstenediol and androstenedione were also increased in fetal testes (P < .05 for both).
Discussion and conclusion: Testicular steroid signatures showed that both steroidogenic Δ4 and Δ5 pathways in the production of testosterone were activated more during prenatal development. Both 7α- and 11β-hydroxylations were predominant, while hydroxylations at C-6, C-15, and C-16 of testosterone and androstenedione were decreased in the fetus. The present GC-MS-based steroid profiling may facilitate understanding of the development of testicular steroidogenesis.. |
| 5. |
Yokoyama, Chikako; Chigi, Yuta; Baba, Takashi; Ohshitanai, Atsushi; Harada, Yumi; Takahashi, Fumiya; Morohashi, Ken-ichirou, Three populations of adult Leydig cells in mouse testes revealed by a novel mouse HSD3B1-specific rat monoclonal antibody, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 10.1016/j.bbrc.2019.02.100, 511, 4, 916-920, 2019.04. |
| 6. |
Katoh-Fukui, Yuko; Baba, Takashi; Sato, Tetsuya; Otake, Hiroyuki; Nagakui-Noguchi, Yuko; Shindo, Miyuki; Suyama, Mikita; Ohkawa, Yasuyuki; Tsumura, Hideki; Morohashi, Ken-ichirou; Fukami, Maki, Mouse polycomb group gene Cbx2 promotes osteoblastic but suppresses adipogenic differentiation in postnatal long bones, BONE, 10.1016/j.bone.2018.10.021, 120, 219-231, 2019.03. |
| 7. |
Inoue M, Baba T, Morohashi KI., Recent progress in understanding the mechanisms of Leydig cell differentiation, Molecular and Cellular Endocrinology, 10.1016, 15;468:39-46, 2018.06. |
| 8. |
Baba T, Otake H, Inoue M, Sato T, Ishihara Y, Moon JY, Tsuchiya M, Miyabayashi K, Ogawa H, Shima Y, Wang L, Sato R, Yamazaki T, Suyama M, Nomura M, Choi MH, Ohkawa Y, Morohashi KI., Ad4BP/SF-1 regulates cholesterol synthesis to boost the production of steroids, Communications Biology, 10.1038/s42003-018-0020-z, 18, 2018.02. |
| 9. |
Shu JS, 馬場 崇, Huang JY, Ogawa H, Hsieh CH, Hu JX, Chen TY, Lin TC, Tsuchiya M, Ken-ichirou Morohashi, Huang BM, Lu FL, Wang CY, Lysosomal activity maintains glycolysis and cyclin E1 expression by mediating Ad4BP/SF-1 stability for proper steroidogenic cell growth, SCIENTIFIC REPORTS, 10.1038/s41598-017-00393-4, 7, 2017.03. |
| 10. |
宍戸祐里菜, 馬場 崇, Sato Tetsuya, Shima Y, Miyabayashi K, 井上 実紀, Akiyama H, Kimura H, Kanai Y, Ishihara Y, Haraguchi S, Miyazaki A, Rozman D, Yamazaki T, Choi MH, Ohkawa, Y, M. Suyama, Ken-ichirou Morohashi, Differential lactate and cholesterol synthetic activities in XY and XX Sertoli cells, SCIENTIFIC REPORTS, 10.1038/srep41912, 7, 2017.02. |
| 11. |
Igarashi M, Takasawa K, Hakoda A, Kanno J, Takada S, Miyado M, 馬場 崇, Ken-ichirou Morohashi, Tajima T, Hata K, Nakabayashi K, Matsubara Y, Sekido R, Ogata T, Kashimada K, Fukami M, Identical NR5A1 Missense Mutations in Two Unrelated 46,XX Individuals with Testicular Tissues, HUMAN MUTATION, 10.1002/humu.23116, 38, 1, 39-42, 2017.01. |
| 12. |
井上実紀, 馬場 崇, 諸橋 憲一郎, Isolation and characterization of fetal Leydig progenitor cells of male mice., Endocrinology, 157, 1222-1233, 2016.01. |
| 13. |
Katoh-Fukui, Yuko; Igarashi, Maki; Nagasaki, Keisuke; Horikawa, Reiko; Nagai, Toshiro; Tsuchiya, Takayoshi; Suzuki, Erina; Miyado, Mami; Hata, Kenichiro; Nakabayashi, Kazuhiko; Hayashi, Keiko; Matsubara, Yoichi; Baba, Takashi; Morohashi, Ken-ichirou; Igarashi, Arisa; Ogata, Tsutomu; Takada, Shuji; Fukami, Maki, Testicular dysgenesis/regression without campomelic dysplasia in patients carrying missense mutations and upstream deletion of SOX9, Mol. Genet. Genom. Med., 10.1002/mgg3.165, 3, 6, 550-557, 2015.11. |
| 14. |
Shima, Yuichi; Matsuzaki, Sawako; Miyabayashi, Kanako; Otake, Hiroyuki; Baba, Takashi; Kato, Shigeaki; Huhtaniemi, Ilpo; Morohashi, Ken-ichirou, Fetal Leydig Cells Persist as an Androgen-Independent Subpopulation in the Postnatal Testis, MOLECULAR ENDOCRINOLOGY, 10.1210/me.2015-1200, 29, 11, 1581-1593, 2015.11. |
| 15. |
Miyabayashi, Kanako; Tokunaga, Kaori; Otake, Hiroyuki; Baba, Takashi; Shima, Yuichi; Morohashi, Ken-ichirou, Heterogeneity of Ovarian Theca and Interstitial Gland Cells in Mice, PLOS ONE, 10.1371/journal.pone.0128352, 10, 6, 2015.06. |
| 16. |
Yokoyama, Atsushi; Igarashi, Katsuhide; Sato, Tetsuya; Takagi, Kiyoshi; Otsuka, Maky, I; Shishido, Yurina; Baba, Takashi; Ito, Ryo; Kanno, Jun; Ohkawa, Yasuyuki; Morohashi, Ken-ichirou; Sugawara, Akira, Identification of Myelin Transcription Factor 1 (MyT1) as a Subunit of the Neural Cell Type-specific Lysine-specific Demethylase 1 (LSD1) Complex, J. Biol. Chem., 10.1074/jbc.M114.566448, 289, 26, 18152-18162, 2014.06, Regulation of spatiotemporal gene expression in higher eukaryotic cells is critical for the precise and orderly development of undifferentiated progenitors into committed cell types of the adult. It is well known that dynamic epigenomic regulation (including chromatin remodeling and histone modifications by transcriptional coregulator complexes) is involved in transcriptional regulation. Precisely how these coregulator complexes exert their cell-type and developing stage-specific activity is largely unknown. In this study, we aimed to isolate the histone demethylase LSD1 complex from neural cells by biochemical purification. In so doing, we identified MyT1 as a novel LSD1 complex component. MyT1 is a neural cell-specific zinc finger factor and it forms a stable multiprotein complex with LSD1 through direct interaction. Target gene analysis using microarray and ChIP assays revealed that the Pten gene was directly regulated by the LSD1-MyT1 complex. Knockdown of either LSD1 or MyT1 derepressed the expression of endogenous target genes and inhibited cell proliferation of a neuroblastoma cell line, Neuro2a. We propose that formation of tissue-specific combinations of coregulator complexes is a critical mechanism for tissue-specific transcriptional regulation.. |
| 17. |
Baba, Takashi; Otake, Hiroyuki; Sato, Tetsuya; Miyabayashi, Kanako; Shishido, Yurina; Wang, Chia-Yih; Shima, Yuichi; Kimura, Hiroshi; Yagi, Mikako; Ishihara, Yasuhiro; Hino, Shinjiro; Ogawa, Hidesato; Nakao, Mitsuyoshi; Yamazaki, Takeshi; Kang, Dongchon; Ohkawa, Yasuyuki; Suyama, Mikita; Chung, Bon-Chu; Morohashi, Ken-Ichirou, Glycolytic genes are targets of the nuclear receptor Ad4BP/SF-1, NATURE COMMUNICATIONS, 10.1038/ncomms4634, 5, 2014.04, Genetic deficiencies in transcription factors can lead to the loss of certain types of cells and tissue. The steroidogenic tissue-specific nuclear receptor Ad4BP/SF-1 (NR5A1) is one such gene, because mice in which this gene is disrupted fail to develop the adrenal gland and gonads. However, the specific role of Ad4BP/SF-1 in these biological events remains unclear. Here we use chromatin immunoprecipitation sequencing to show that nearly all genes in the glycolytic pathway are regulated by Ad4BP/SF-1. Suppression of Ad4BP/SF-1 by small interfering RNA reduces production of the energy carriers ATP and nicotinamide adenine dinucleotide phosphate, as well as lowers expression of genes involved in glucose metabolism. Together, these observations may explain tissue dysgenesis as a result of Ad4BP/SF-1 gene disruption in vivo. Considering the function of estrogen-related receptor α, the present study raises the possibility that certain types of nuclear receptors regulate sets of genes involved in metabolic pathways to generate energy carriers.. |
| 18. |
Miyabayashi, Kanako; Katoh-Fukui, Yuko; Ogawa, Hidesato; Baba, Takashi; Shima, Yuichi; Sugiyama, Noriyuki; Kitamura, Kunio; Morohashi, Ken-ichirou, Aristaless Related Homeobox Gene, Arx, Is Implicated in Mouse Fetal Leydig Cell Differentiation Possibly through Expressing in the Progenitor Cells, PLoS One., 10.1371/journal.pone.0068050, 8, 6, 2013.06, Development of the testis begins with the expression of the SRY gene in pre-Sertoli cells. Soon after, testis cords containing Sertoli and germ cells are formed and fetal Leydig cells subsequently develop in the interstitial space. Studies using knockout mice have indicated that multiple genes encoding growth factors and transcription factors are implicated in fetal Leydig cell differentiation. Previously, we demonstrated that the Arx gene is implicated in this process. However, how ARX regulates Leydig cell differentiation remained unknown. In this study, we examined Arx KO testes and revealed that fetal Leydig cell numbers largely decrease throughout the fetal life. Since our study shows that fetal Leydig cells rarely proliferate, this decrease in the KO testes is thought to be due to defects of fetal Leydig progenitor cells. In sexually indifferent fetal gonads of wild type, ARX was expressed in the coelomic epithelial cells and cells underneath the epithelium as well as cells at the gonad-mesonephros border, both of which have been described to contain progenitors of fetal Leydig cells. After testis differentiation, ARX was expressed in a large population of the interstitial cells but not in fetal Leydig cells, raising the possibility that ARX-positive cells contain fetal Leydig progenitor cells. When examining marker gene expression, we observed cells as if they were differentiating into fetal Leydig cells from the progenitor cells. Based on these results, we propose that ARX acts as a positive factor for differentiation of fetal Leydig cells through functioning at the progenitor stage.. |
| 19. |
Shima, Yuichi; Miyabayashi, Kanako; Haraguchi, Shogo; Arakawa, Tatsuhiko; Otake, Hiroyuki; Baba, Takashi; Matsuzaki, Sawako; Shishido, Yurina; Akiyama, Haruhiko; Tachibana, Taro; Tsutsui, Kazuyoshi; Morohashi, Ken-ichirou, Contribution of Leydig and Sertoli Cells to Testosterone Production in Mouse Fetal Testes, Mol. Endocrinol., 10.1210/me.2012-1256, 27, 1, 63-73, 2013.01. |
| 20. |
Shima, Yuichi; Miyabayashi, Kanako; Baba, Takashi; Otake, Hiroyuki; Katsura, Yukako; Oka, Sanae; Zubair, Mohamad; Morohashi, Ken-inchirou, Identification of an Enhancer in the Ad4BP/SF-1 Gene Specific for Fetal Leydig Cells (vol 153, pg 417, 2012), Endocrinology, 10.1210/en.2012-1948, 153, 11, 5686-5686, 2012.11. |
| 21. |
Katoh-Fukui Y, Miyabayashi K, Komatsu T, Owaki A, Baba T, Shima Y, Kidokoro T, Kanai Y, Schedl A, Wilhelm D, Koopman P, Okuno Y, Morohashi K., Cbx2, a polycomb group gene, is required for Sry gene expression in mice, Endocrinology, 10.1210/en.2011-1055, 153, 913-924, 2012.01. |
| 22. |
Keiko Nohara, Takashi Baba, Hikari Murai, Yayoi Kobayashi, Takehiko Suzuki, Yukiyo Tateishi, Michiyo Matsumoto, Noriko Nishimura, and Tomoharu Sano, Genomic DNA methylation in the mouse liver is affected by methyl deficiency and arsenic in a sex- and a dietary-fat-content-dependent manner, Arch. Toxicol., 85, 653-661, 2011.01. |
| 23. |
Kusaka, Masatomo; Katoh-Fukui, Yuko; Ogawa, Hidesato; Miyabayashi, Kanako; Baba, Takashi; Shima, Yuichi; Sugiyama, Noriyuki; Sugimoto, Yukihiko; Okuno, Yasushi; Kodama, Ryuji; Iizuka-Kogo, Akiko; Senda, Takao; Sasaoka, Toshikuni; Kitamura, Kunio; Aizawa, Shinichi; Morohashi, Ken-ichirou, Abnormal Epithelial Cell Polarity and Ectopic Epidermal Growth Factor Receptor (EGFR) Expression Induced in Emx2 KO Embryonic Gonads, Endocrinology, 10.1210/en.2010-0915, 151, 12, 5893-5904, 2010.12. |
| 24. |
Sato, Yuko; Baba, Takashi; Zubair, Mohamad; Miyabayashi, Kanako; Toyama, Yoshiro; Maekawa, Mamiko; Owaki, Akiko; Mizusaki, Hirofumi; Sawamura, Tatsuya; Toshimori, Kiyotaka; Morohashi, Ken-Ichirou; Kato-Fukui, Yuko, Importance of forkhead transcription factor Fkhl18 for development of testicular vasculature, Mol. Reprod. Dev., 10.1002/mrd.20888, 75, 9, 1361-1371, 2008.09. |
| 25. |
Fukami, Maki; Wada, Yuka; Okada, Michiyo; Kato, Fumiko; Katsumata, Noriyuki; Baba, Takashi; Morohashi, Ken-ichirou; Laporte, Jocelyn; Kitagawa, Motoo; Ogata, Tsutomu, Mastermind-like domain-containing 1 (MAMLD1 or CXorf6) transactivates the Hes3 promoter, augments testosterone production, and contains the SF1 target sequence, J. Biol. Chem., 283, 9, 5525-5532, 2008.02. |
| 26. |
Kurokawa H, Saito D, Nakamura S, Fukui-katoh Y, Ohta K, Baba T, Morohashi KI, *Tanaka M, Germ Cells are essential for sexually dimorphic gonadogenesis, Proc. Natl. Acad. Sci. USA, 104, 16958-16953, 2007.10. |
| 27. |
Baba, T; Mimura, J; Nakamura, N; Harada, N; Yamamoto, M; Morohashi, K; Fujii-Kuriyama, Y, Intrinsic function of the aryl hydrocarbon (Dioxin) receptor as a key factor in female reproduction, Mol. Cell. Biol., 10.1128/MCB.25.22.10040-10051.2005, 25, 22, 10040-10051, 2005.11. |
| 28. |
Baba, T; Mimura, J; Gradin, K; Kuroiwa, A; Watanabe, T; Matsuda, Y; Inazawa, J; Sogawa, K; Fujii-Kuriyama, Y, Structure and expression of the Ah receptor repressor gene, J. Biol. Chem., 276, 35, 33101-33110, 2001.08. |
| 29. |
Baba, T.; Shima, Y.; Owaki, A.; Mimura, J.; Oshima, M.; Fujii-Kuriyama, Y.; Morohashi, K. -i., Disruption of aryl hydrocarbon receptor (AhR) induces regression of the seminal vesicle in aged male mice, Sex. Dev., 10.1159/000117714, 2, 1, 1-11. |
| 30. |
Morohashi, K.; Baba, T.; Tanaka, M., Steroid Hormones and the Development of Reproductive Organs, Sex. Dev., 10.1159/000342272, 7, 1-3, 61-79, It has been more than 150 years since the physiological function of androgen was reported for the first time in fowl. This finding has served as a basis for many studies focusing on steroid hormones from various aspects. These studies have significantly enhanced our knowledge about the structures of steroid hormones, their synthetic pathways, enzymes involved in the synthetic pathways, steroid hormone-specific receptors, actions of steroid hormones through receptor binding, and the differentiation of steroidogenic cells. However, there are still many attractive and important issues in these areas, some of which are currently being addressed. In this review, we trace the history and findings of the previous studies on steroid hormones, summarize our present understanding in this area, and discuss issues that remain to be elucidated.. |
| 31. |
宮林 香奈子, Yuichi Shima, 井上 実紀, Sato Tetsuya, 馬場 崇, Ohkawa, Y, M. Suyama, Ken-ichirou Morohashi, Alterations in Fetal Leydig Cell Gene Expression during Fetal and Adult Development, SEXUAL DEVELOPMENT, 10.1159/000453323, 11, 2, 53-63. |
| 32. |
Li B, 馬場 崇, Miyabayashi K, Sato Tetsuya, Shima Y, Ichinose T, Miura D, Ohkawa, Y, M. Suyama, Ken-ichirou Morohashi, Role of Ad4-binding protein/steroidogenic factor 1 in regulating NADPH production in adrenocortical Y-1 cells, ENDOCRINE JOURNAL, 64, 3, 315-324. |
