九州大学 研究者情報
論文一覧
馬場 崇(ばば たかし) データ更新日:2022.06.25

准教授 /  医学研究院 分子生命科学系部門 性差生物学(分子生物学)


原著論文
1. Yasuko Fujisawa, Hiroyuki Ono, Alu Konno, Ikuko Yao, Hiroaki Itoh, Takashi Baba, Ken-ichirou Morohashi, Yuko Katoh-Fukui, Mami Miyado, Maki Fukami, Tsutomu Ogata, Intrauterine Hyponutrition Reduces Fetal Testosterone Production and Postnatal Sperm Count in the Mouse, JOURNAL OF THE ENDOCRINE SOCIETY, 10.1210/jendso/bvac022, 6(4):bvac022, 2022.04.
2. Antonius Christianto, Takashi Baba, Fumiya Takahashi, Kai Inui, Miki Inoue, Mikita Suyama, Yusuke Ono, Yasuyuki Ohkawa, Ken-Ichirou Morohashi, Sex differences in metabolic pathways are regulated by Pfkfb3 and Pdk4 expression in rodent muscle, COMMUNICATIONS BIOLOGY, 10.1038/s42003-021-02790-y, 4, 1, 2021.11.
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. Morohashi KI, Inoue M, Baba T, Coordination of Multiple Cellular Processes by NR5A1/Nr5a1, Endocrinol Metab (Seoul), 10.3803/EnM.2020.402., 35(4):756-764., 2020.12.
5. 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..
6. 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.
7. 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.
8. 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.
9. Miki Inoue, Takashi Baba, Ken ichirou Morohashi, Recent progress in understanding the mechanisms of Leydig cell differentiation, Molecular and Cellular Endocrinology, 10.1016/j.mce.2017.12.013, 468, 39-46, 2018.06, [URL], Leydig cells in fetal and adult testes play pivotal roles in eliciting male characteristics by producing androgen. Although numerous studies of Leydig cells have been performed, the mechanisms for differentiation of the two cell types (fetal Leydig and adult Leydig cells), their developmental and functional relationship, and their differential characteristics remain largely unclear. Based on recent technical progress in genome-wide analysis and in vitro investigation, novel and fascinating observations concerning the issues above have been obtained. Focusing on fetal and adult Leydig cells, this review summarizes the recent progress that has advanced our understanding of the cells..
10. Ken Ichirou Morohashi, Miki Inoue, Bing Li, Takashi Baba, Regulation of metabolic pathways in steroidogenic cells by Ad4BP/SF-1, Cell Biology of the Ovary
Stem Cells, Development, Cancer, and Clinical Aspects
, 10.1007/978-981-10-7941-2_3, 35-43, 2018.06, [URL], Ad4BP/SF-1 (NR5A1), a member of the nuclear receptor superfamily, is known to play crucial roles in the regulation of steroidogenesis in the gonads and adrenal cortex, and many studies have demonstrated that all steroidogenic genes are direct targets of Ad4BP/SF-1. In addition, in vivo KO studies demonstrated that no steroidogenic organs formed in gene-disrupted mice, strongly suggesting that Ad4BP/SF-1 is essential for the development of the gonads and adrenal gland. However, it remains unclear how Ad4BP/SF-1 regulates the development of the steroidogenic organs and which additional non-steroidogenic genes are targeted. We surveyed the target genes of Ad4BP/SF-1 in steroidogenic cells by mRNA deep sequencing and ChIP-sequence analyses using an Ad4BP/SF-1 antibody. Nearly all genes in energy-producing glycolytic pathways were found to be regulated by Ad4BP/SF-1. We also showed that the key genes implicated in NADPH production are the direct targets. Since sufficient supplies of ATP and NADPH are necessary for cellular survival and production of steroids, Ad4BP/SF-1 possibly orchestrates tissue-specific steroidogenic pathway and these housekeeping metabolic pathways..
11. 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.
12. Takashi Baba, The role of Ad4BP/SF-1 in the development of adrenal gland and the synthesis of adrenal steroid, Japanese Journal of Clinical Urology, 72, 6, 424-429, 2018.01.
13. 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.
14. 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.
15. 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.
16. Bing Li, Takashi Baba, Kanako Miyabayashi, Tetsuya Sato, Yuichi Shima, Tomomi Ichinose, Daisuke Miura, Yasuyuki Ohkawa, Mikita Suyama, Ken Ichirou Morohashi, Role of Ad4-binding protein/steroidogenic factor 1 in regulating NADPH production in adrenocortical Y-1 cells, Endocrine Journal, 10.1507/endocrj.EJ16-0467, 64, 3, 315-324, 2017.01, [URL], Ad4-binding protein/steroidogenic factor 1 (Ad4BP/SF-1), a member of the nuclear receptor superfamily, is expressed in steroidogenic cells and regulates all steroidogenic gene expression. We recently employed mRNA and chromatin immunoprecipitation sequence (ChIP-seq) to demonstrate that Ad4BP/SF-1 directly regulates the expression of nearly all glycolytic genes. The pentose phosphate pathway (PPP) contributes to the production of nicotinamide adenine dinucleotide phosphate (NADPH). Although the expression of PPP genes and intracellular NADPH were decreased by Ad4BP/SF-1 knockdown, these genes were not the direct targets of Ad4BP/SF-1. This study therefore investigates whether Ad4BP/SF-1 directly regulates genes implicated in NADPH production. Examination of previously published data sets of mRNA sequence (mRNA-seq) and ChIP-seq strongly suggested a possibility that other NADPH-producing genes, such as malic enzyme 1 (Me1) and methylenetetrahydrofolate dehydrogenase 2 (Mthfd2), are the direct targets of Ad4BP/SF-1. Reporter gene assays and determination of intracellular NADPH concentration supported the notion that Ad4BP/SF-1 regulates NADPH production by regulating these genes. NADPH is required for macromolecule synthesis of compounds such as steroids, and for detoxification of reactive oxygen species. When synthesizing steroid hormones, steroidogenic cells consume NADPH through enzymatic reactions mediated by steroidogenic P450s. NADPH is also consumed through elimination of reactive oxygen species produced as the byproducts of the P450 reactions. Overall, Ad4BP/SF-1 potentially maintains the intracellular NADPH level through cooperative regulation of genes involved in the biological processes for consumption and supply..
17. Miki Inoue, Yuichi Shima, Kanako Miyabayashi, Kaori Tokunaga, Tetsuya Sato, Takashi Baba, Yasuyuki Ohkawa, Haruhiko Akiyama, Mikita Suyama, Ken Ichirou Morohashi, Isolation and characterization of Fetal Leydig progenitor cells of male mice, Endocrinology, 10.1210/en.2015-1773, 157, 3, 1222-1233, 2016.03, [URL], Fetal and adult Leydig cells develop in mammalian prenatal and postnatal testes, respectively. In mice, fetal Leydig cells (FLCs) emergeintheinterstitial spaceofthe testisatembryonic day 12.5 and thereafter increase in number, possibly through differentiation from progenitor cells. However, the progenitor cells have not yet been identified. Previously, we established transgenic mice in which FLCs are labeled strongly with enhanced green fluorescent protein (EGFP). Interestingly, fluorescence-activated cell sorting provided us with weakly EGFP-labeled cells as well as strongly EGFP-labeled FLCs. In vitro reconstruction of fetal testes demonstrated that weakly EGFP-labeled cells contain FLC progenitors. Transcriptome from the 2 cell populations revealed, as expected, marked differences in the expression of genes required for growth factor/receptor signaling and steroidogenesis. In addition, genes for energy metabolisms such as glycolytic pathways and the citrate cycle were activated in strongly EGFP-labeled cells, suggesting that metabolism is activated during FLC differentiation..
18. 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.
19. 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.
20. 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.
21. 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.
22. 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..
23. 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..
24. Ken Ichirou Morohashi, Takashi Baba, Regulation of metabolism by orphan receptor regulone, Seikagaku, 86, 6, 719-725, 2014.01.
25. Ken-Ichirou Morohashi, Takashi Baba, M. Tanaka, Steroid hormones and the development of reproductive organs., Sexual Development, 7, 1-3, 61-79, 2013.09, 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..
26. 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..
27. 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.
28. 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.
29. 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.
30. Yuichi Shima, Kanako Miyabayashi, Takashi Baba, Hiroyuki Otake, Sanae Oka, Mohamad Zubair, Ken Ichirou Morohashi, Identification of an enhancer in the Ad4BP/SF-1 gene specific for fetal leydig cells, Endocrinology, 10.1210/en.2011-1407, 153, 1, 417-425, 2012.01, [URL], Adrenal 4 binding protein/steroidogenic factor 1 (Ad4BP/SF-1) (Nr5a1) is a nuclear receptor essential for reproductive tissue development and endocrine regulation. This factor is expressed in steroidogenic tissues (e.g. adrenal glands and gonads), and expression of this factor is tightly regulated in a tissue and cell type-specific manner. Our previous studies have identified tissue and cell type-specific enhancers in the introns of the Ad4BP/SF-1 gene in fetal adrenal glands, ventromedial hypothalamus, and pituitary gonadotrope. Characterization of the enhancers had provided new insights into tissue and cell development. However, these studies have failed to identify any gonad-specific enhancer. Here, we identified a fetal Leydig cell-specific enhancer in the upstream region of the mouse Ad4BP/SF-1 gene using transgenic mouse assays. Alignment of the upstream regions among vertebrate animal species demonstrated that the enhancer consisted of three conserved regions, whereby the most highly conserved region contained an Ad4BP/SF-1 binding sequence and an E-box. Mutation of each sequence abolished the enhancer activity and led to a loss of reporter gene expression. These results suggested that Ad4BP/SF-1 gene expression in the fetal Leydig cell is regulated by a yet unidentified E-box binding protein(s) and by an autoregulatory loop formed by Ad4BP/SF-1. Although fetal Leydig cells have been thought to play crucial roles for masculinization of various fetal tissues through androgen production, other functions have remained elusive. Our identification of a fetal Leydig cell-specific enhancer in the Ad4BP/SF-1 gene would be a powerful tool to address these gaps in the knowledge base..
31. 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.
32. 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.
33. 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.
34. 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.
35. Maki Fukami, Yuka Wada, Michiyo Okada, Fumiko Kato, Noriyuki Katsumata, Takashi Baba, Ken Ichirou Morohashi, Jocelyn Laporte, Motoo Kitagawa, Tsutomu Ogata, Mastermind-like domain-containing 1 (MAMLD1 or CXorf6) transactivates the Hes3 promoter, augments testosterone production, and contains the SF1 target sequence, Journal of Biological Chemistry, 10.1074/jbc.M703289200, 283, 9, 5525-5532, 2008.02, [URL], Although chromosome X open reading frame 6 (CXorf6) has been shown to be a causative gene for hypospadias, its molecular function remains unknown. To clarify this, we first examined CXorf6 protein structure, identifying homology to mastermind-like 2 (MAML2) protein, which functions as a co-activator in canonical Notch signaling. Transactivation analysis for wild-type CXorf6 protein by luciferase assays showed that CXorf6 significantly transactivated the promoter of a noncanonical Notch target gene hairy/enhancer of split 3 (Hes3) without demonstrable DNA-binding capacity. Transactivation analysis was also performed for the previously described three apparently pathologic nonsense mutations, indicating that E124X and Q197X proteins had no transactivation function, whereas R653X protein retained a nearly normal transactivation function. Subcellular localization analysis revealed that wild-type and R653X proteins co-localized with MAML2 protein in nuclear bodies, whereas E124X and Q197X proteins were incapable of localizing to nuclear bodies. Thus, further studies were performed for R653X, revealing the occurrence of nonsense mediated mRNA decay in vivo. Next, transient knockdown of CXorf6 was performed using small interfering RNA, showing reduced testosterone production in mouse Leydig tumor cells. Furthermore, steroidogenic factor 1 (SF1) protein bound to a specific sequence in the upstream of the CXorf6 coding region and exerted a transactivation activity. These results suggest that CXorf6 transactivates the Hes3 promoter, augments testosterone production, and contains the SF1 target sequence, thereby providing the first clue to clarify the biological role of CXorf6. We designate CXorf6 as MAMLD1 (mastermind-like domain-containing 1) based on its characteristic structure..
36. 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.
37. Hiromi Kurokawa, Daisuke Saito, Shuhei Nakamura, Yuko Katoh-Fukui, Kohei Ohta, Takashi Baba, Ken Ichiro Morohashi, Minoru Tanaka, Germ cells are essential for sexual dimorphism in the medaka gonad, Proceedings of the National Academy of Sciences of the United States of America, 10.1073/pnas.0609932104, 104, 43, 16958-16963, 2007.10, [URL], To further elucidate the roles of germ cells in the sex differentiation of gonads, we have used the medaka, a teleost fish, to generate mutants that lack germ cells from the onset of gonadogenesis by the morpholino-mediated knockdown of cxcr4. The resulting germ-cell-deficient medaka show female-to-male sex reversal of their secondary sex characteristics, accompanied by increased levels of androgen and reduced levels of estrogen. A failure to maintain granulosa cells or estrogen-producing cells also occurs at early stages of sex differentiation in the cxcr4 morphants, before the initiation of gonadal morphogenesis. In contrast, androgen-producing cells are unaffected in germ-cell-deficient medaka of either sex. In addition, a single tube-like gonad that expresses male-specific genes is formed in these mutants irrespective of the genetic sex. Significantly, each of these mutant phenotypes occurs in a somatic cell-autonomous manner, suggesting that gonadal somatic cells are predisposed toward male development in the absence of germ cells. This highlights the importance of germ cells in the sexual dimorphism of the gonads..
38. 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.
39. Yoshiaki Fujii-Kuriyama, Junsei Mimura, Takashi Baba, Keiko Numayama-Tsuruta, Kazuhiro Sogawa, Action mechanism of dioxin receptor, Nippon Nogeikagaku Kaishi, 10.1271/nogeikagaku1924.76.1073, 76, 11, 1073-1075, 2002.01, [URL].
40. 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.
41. Takashi Baba, Junsei Mimura, Katarina Gradin, Asato Kuroiwa, Takafumi Watanabe, Yoichi Matsuda, Johji Inazawa, Kazuhiro Sogawa, Yoshiaki Fujii-Kuriyama, Structure and Expression of the Ah Receptor Repressor Gene, Journal of Biological Chemistry, 10.1074/jbc.M011497200, 276, 35, 33101-33110, 2001.08, [URL], The aryl hydrocarbon receptor (AhR) repressor (AhRR) gene has been isolated and characterized from a mouse genomic library. The gene is distributed as 11 exons in a total length of about 60 kilobase pairs. Fluorescence in situ hybridization analysis has shown that the AhRR gene is located at mouse chromosome 13C2, at rat chromosome 1p11.2, and at human chromosome 5p15.3. The AhRR gene has a TATA-less promoter and several transcription start sites. In addition, putative regulatory DNA sequences such as xenobiotic responsive element (XRE), GC box, and NF-κB-binding sites have been identified in the 5′-upstream region of the AhRR gene. Transient transfection analyses of HeLa cells with reporter genes that contain deletions and point mutations in the AhRR promoter revealed that all three XREs mediated the inducible expression of the AhRR gene by 3-methylcholanthrene treatment, and furthermore, GC box sequences were indispensable for a high level of inducible expression and for constitutive expression. Moreover, by using gel mobility shift assays we were able to show that the AhR/Arnt heterodimer binds to the XREs with very low affinity, which is due to three varied nncleotides outside the XRE core sequence. We have also shown that Sp1 and Sp3 can bind to the GC boxes. Finally, both transient transfection analysis and gel mobility shift assay revealed that the AhRR gene is up-regulated by a p65/p50 heterodimer that binds to the NF-κB site when the cells has been exposed to 12-O-tetradecanoylphorbol-13-acetate, and this inducible expression was further enhanced by co-treatment of 12-O-tetradecanoylphorbol-13-acetate and 3-methylcholanthrene..
42. 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.
43. 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..
44. 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.
45. 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.

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