SON YOULEE
| Institute for Genetic Medicine Molecular Pathogenesis | Lecturer |
Last Updated :2025/06/07
■Researcher basic information
Researchmap personal page
Home Page URL
Researcher number
- 10605306
J-Global ID
Educational Organization
- Master's degree program, Graduate School of Medicine
- Doctoral (PhD) degree program, Graduate School of Medicine
■Career
■Research activity information
Papers
- Metabolic Regulation by the Hypothalamic Neuropeptide, Gonadotropin-Inhibitory Hormone at Both the Central and Peripheral Levels
You Lee Son, Simone L. Meddle, Yasuko Tobari
Cells, 14, 4, 267, MDPI AG, 12 Feb. 2025, [Peer-reviewed], [Corresponding author]
Scientific journal, Gonadotropin-inhibitory hormone (GnIH) is well-established as a negative regulator of reproductive physiology and behavior across vertebrates, acting on the hypothalamic–pituitary–gonadal (HPG) axis; however, recent data have also demonstrated its involvement in the control of metabolic processes. GnIH neurons and fibers have been identified in hypothalamic regions associated with feeding behavior and energy homeostasis, with GnIH receptors being expressed throughout the hypothalamus. GnIH does not act alone in the hypothalamus, but rather interacts with the melanocortin system, as well as with other neuropeptides. GnIH and its receptors are also expressed in peripheral tissues involved in important metabolic functions. Therefore, the local action of GnIH in peripheral organs, including the pancreas, gastrointestinal tract, gonad, and adipose tissue, is also suggested. This review aims to provide a comprehensive summary of the emerging role of GnIH in metabolic regulation at both the central and peripheral levels. - Regulation of stress response on the hypothalamic-pituitary-gonadal axis via gonadotropin-inhibitory hormone.
You Lee Son, Takayoshi Ubuka, Kazuyoshi Tsutsui
Frontiers in neuroendocrinology, 64, 100953, Jan. 2022, [Peer-reviewed], [Corresponding author], [International Magazine]
English, Scientific journal, Under stressful condition, reproductive function is impaired due to the activation of various components of the hypothalamic-pituitaryadrenal (HPA) axis, which can suppress the activity of the hypothalamic-pituitary-gonadal (HPG) axis at multiple levels. A hypothalamic neuropeptide, gonadotropin-inhibitory hormone (GnIH) is a key negative regulator of reproduction that governs the HPG axis. Converging lines of evidence have suggested that different stress types and their duration, such as physical or psychological, and acute or chronic, can modulate the GnIH system. To clarify the sensitivity and reactivity of the GnIH system in response to stress, we summarize and critically review the available studies that investigated the effects of various stressors, such as restraint, nutritional/metabolic and social stress, on GnIH expression and/or its neuronal activity leading to altered HPG action. In this review, we focus on GnIH as the potential novel mediator responsible for stress-induced reproductive dysfunction. - Isoform-selective regulation of mammalian cryptochromes.
Simon Miller, You Lee Son, Yoshiki Aikawa, Eri Makino, Yoshiko Nagai, Ashutosh Srivastava, Tsuyoshi Oshima, Akiko Sugiyama, Aya Hara, Kazuhiro Abe, Kunio Hirata, Shinya Oishi, Shinya Hagihara, Ayato Sato, Florence Tama, Kenichiro Itami, Steve A Kay, Megumi Hatori, Tsuyoshi Hirota
Nature chemical biology, 16, 6, 676, 685, 30 Mar. 2020, [Peer-reviewed], [Lead author], [International Magazine]
English, Scientific journal, CRY1 and CRY2 are essential components of the circadian clock controlling daily physiological rhythms. Accumulating evidences indicate distinct roles of these highly homologous proteins, in addition to redundant functions. Therefore, the development of isoform-selective compounds represents an effective approach towards understanding the similarities and differences of CRY1 and CRY2 by controlling each isoform individually. We conducted phenotypic screenings of circadian clock modulators, and identified KL101 and TH301 that selectively stabilize CRY1 and CRY2, respectively. Crystal structures of CRY-compound complexes revealed conservation of compound-binding sites between CRY1 and CRY2. We further discovered a unique mechanism underlying compound selectivity in which the disordered C-terminal region outside the pocket was required for the differential effects of KL101 and TH301 against CRY isoforms. By using these compounds, we found a new role of CRY1 and CRY2 as enhancers of brown adipocyte differentiation, providing the basis of CRY-mediated regulation of energy expenditure. - Molecular Mechanisms of Gonadotropin-Inhibitory Hormone (GnIH) Actions in Target Cells and Regulation of GnIH Expression
You Lee Son, Takayoshi Ubuka, Kazuyoshi Tsutsui
Frontiers in Endocrinology, 10, 110, Frontiers Media SA, 25 Feb. 2019, [Peer-reviewed], [Corresponding author], [International Magazine]
English, Scientific journal, Since gonadotropin-inhibitory hormone (GnIH) was discovered in 2000 as the first hypothalamic neuropeptide that actively inhibits gonadotropin release, researches conducted for the last 18 years have demonstrated that GnIH acts as a pronounced negative regulator of reproduction. Inhibitory effect of GnIH on reproduction is mainly accomplished at hypothalamic-pituitary levels; gonadotropin-releasing hormone (GnRH) neurons and gonadotropes are major targets of GnIH action based on the morphological interaction with GnIH neuronal fibers and the distribution of GnIH receptor. Here, we review molecular studies mainly focusing on the signal transduction pathway of GnIH in target cells, GnRH neurons, and gonadotropes. The use of well-defined cellular model systems allows the mechanistic study of signaling pathway occurring in target cells by demonstrating the direct cause-and-effect relationship. The insights gained through studying molecular mechanism of GnIH action contribute to deeper understanding of the mechanism of how GnIH communicates with other neuronal signaling systems to control our reproductive function. Reproductive axis closely interacts with other endocrine systems, thus GnIH expression levels would be changed by adrenal and thyroid status. We also briefly review molecular studies investigating the regulatory mechanisms of GnIH expression to understand the role of GnIH as a mediator between adrenal, thyroid and gonadal axes. - Review: Structure, function and evolution of GnIH
Kazuyoshi Tsutsui, Tomohiro Osugi, You Lee Son, Takayoshi Ubuka
General and Comparative Endocrinology, 264, 48, 57, Elsevier BV, Aug. 2018, [Peer-reviewed], [International Magazine]
English, Scientific journal, Neuropeptides that possess the Arg-Phe-NH2 motif at their C-termini (i.e., RFamide peptides) have been characterized in the nervous system of both invertebrates and vertebrates. In vertebrates, RFamide peptides make a family and consist of the groups of gonadotropin-inhibitory hormone (GnIH), neuropeptide FF (NPFF), prolactin-releasing peptide (PrRP), kisspeptin (kiss1 and kiss2), and pyroglutamylated RFamide peptide/26RFamide peptide (QRFP/26RFa). It now appears that these vertebrate RFamide peptides exert important neuroendocrine, behavioral, sensory, and autonomic functions. In 2000, GnIH was discovered as a novel hypothalamic RFamide peptide inhibiting gonadotropin release in quail. Subsequent studies have demonstrated that GnIH acts on the brain and pituitary to modulate reproductive physiology and behavior across vertebrates. To clarify the origin and evolution of GnIH, the existence of GnIH was investigated in agnathans, the most ancient lineage of vertebrates, and basal chordates, such as tunicates and cephalochordates (represented by amphioxus). This review first summarizes the structure and function of GnIH and other RFamide peptides, in particular NPFF having a similar C-terminal structure of GnIH, in vertebrates. Then, this review describes the evolutionary origin of GnIH based on the studies in agnathans and basal chordates. - Discovery of GnIH and Its Role in Hypothyroidism-Induced Delayed Puberty
You Lee Son
Endocrinology, 159, 1, 62, 68, The Endocrine Society, 01 Jan. 2018, [Peer-reviewed]
English, Scientific journal,Abstract
It is known that hypothyroidism delays puberty in mammals. Interaction between the hypothalamo-pituitary-thyroid (HPT) and hypothalamo-pituitary-gonadal (HPG) axes may be important processes in delayed puberty. Gonadotropin-inhibitory hormone (GnIH) is a newly discovered hypothalamic neuropeptide that inhibits gonadotropin synthesis and release in quail. It now appears that GnIH is conserved across various mammals and primates, including humans, and inhibits reproduction. We have further demonstrated that GnIH is involved in pubertal delay induced by thyroid dysfunction in female mice. Hypothyroidism delays pubertal onset with the increase in hypothalamic GnIH expression and the decrease in circulating gonadotropin and estradiol levels. Thyroid status regulates GnIH expression by epigenetic modification of the GnIH promoter region. Furthermore, knockout of GnIH gene abolishes the effect of hypothyroidism on delayed pubertal onset. Accordingly, it is considered that GnIH is a mediator of pubertal disorder induced by thyroid dysfunction. This is a novel function of GnIH that interacts between the HPT-HPG axes in pubertal onset delay. This mini-review summarizes the structure, expression, and function of GnIH and highlights the action of GnIH in pubertal disorder induced by thyroid dysfunction. - Involvement of gonadotropin-inhibitory hormone in pubertal disorders induced by thyroid status
You Lee Son
Scientific Reports, 7, 1, 1042, Springer Science and Business Media LLC, Dec. 2017, [Peer-reviewed], [Lead author, Corresponding author]
English, Scientific journal - Inhibitory action of gonadotropin-inhibitory hormone on the signaling pathways induced by kisspeptin and vasoactive intestinal polypeptide in GnRH neuronal cell line, GT1-7
You Lee Son, Takayoshi Ubuka, Tomoko Soga, Kazutoshi Yamamoto, George E. Bentley, Kazuyoshi Tsutsui
FASEB JOURNAL, 30, 6, 2198, 2210, Jun. 2016, [Peer-reviewed]
English, Scientific journal - Molecular, cellular, morphological, physiological and behavioral aspects of gonadotropin-inhibitory hormone
Takayoshi Ubuka, You Lee Son, Kazuyoshi Tsutsui
General and Comparative Endocrinology, 227, 27, 50, Elsevier BV, Feb. 2016, [Peer-reviewed], [International Magazine]
English, Scientific journal, Gonadotropin-inhibitory hormone (GnIH) is a hypothalamic neuropeptide that was isolated from the brains of Japanese quail in 2000, which inhibited luteinizing hormone release from the anterior pituitary gland. Here, we summarize the following fifteen years of researches that investigated on the mechanism of GnIH actions at molecular, cellular, morphological, physiological, and behavioral levels. The unique molecular structure of GnIH peptide is in its LPXRFamide (X=L or Q) motif at its C-terminal. The primary receptor for GnIH is GPR147. The cell signaling pathway triggered by GnIH is initiated by inhibiting adenylate cyclase and decreasing cAMP production in the target cell. GnIH neurons regulate not only gonadotropin synthesis and release in the pituitary, but also regulate various neurons in the brain, such as GnRH1, GnRH2, dopamine, POMC, NPY, orexin, MCH, CRH, oxytocin, and kisspeptin neurons. GnIH and GPR147 are also expressed in gonads and they may regulate steroidogenesis and germ cell maturation in an autocrine/paracrine manner. GnIH regulates reproductive development and activity. In female mammals, GnIH may regulate estrous or menstrual cycle. GnIH is also involved in the regulation of seasonal reproduction, but GnIH may finely tune reproductive activities in the breeding seasons. It is involved in stress responses not only in the brain but also in gonads. GnIH may inhibit male socio-sexual behavior by stimulating the activity of cytochrome P450 aromatase in the brain and stimulates feeding behavior by modulating the activities of hypothalamic and central amygdala neurons. - RFamide peptides in agnathans and basal chordates
Tomohiro Osugi, You Lee Son, Takayoshi Ubuka, Honoo Satake, Kazuyoshi Tsutsui
General and Comparative Endocrinology, 227, 94, 100, Elsevier BV, Feb. 2016, [Peer-reviewed], [International Magazine]
English, Scientific journal, Since a peptide with a C-terminal Arg-Phe-NH2 (RFamide peptide) was first identified in the ganglia of the venus clam in 1977, RFamide peptides have been found in the nervous system of both invertebrates and vertebrates. In vertebrates, the RFamide peptide family includes gonadotropin-inhibitory hormone (GnIH), neuropeptide FF (NPFF), prolactin-releasing peptide (PrRP), pyroglutamylated RFamide peptide/26RFamide peptide (QRFP/26RFa), and kisspeptins (kiss1 and kiss2). They are involved in important functions such as the release of hormones, regulation of sexual or social behavior, pain transmission, reproduction, and feeding. In contrast to tetrapods and jawed fish, the information available on RFamide peptides in agnathans and basal chordates is limited, thus preventing further insights into the evolution of RFamide peptides in vertebrates. In this review, we focus on the previous research and recent advances in the studies on RFamide peptides in agnathans and basal chordates. In agnathans, the genes encoding GnIH, NPFF, and PrRP precursors and the mature peptides have been identified in lamprey (Petromyzon marinus) and hagfish (Paramyxine atami). Putative kiss1 and kiss2 genes have also been found in the genome database of lamprey. In basal chordates, namely, in amphioxus (Branchiostoma japonicum), a common ancestral form of GnIH and NPFF genes and their mature peptides, as well as the ortholog of the QRFP gene have been identified. The studies revealed that the number of orthologs of vertebrate RFamide peptides present in agnathans and basal chordates is greater than expected, suggesting that the vertebrate RFamide peptides might have emerged and expanded at an early stage of chordate evolution. - Contribution of GnIH Research to the Progress of Reproductive Neuroendocrinology
Kazuyoshi Tsutsui, Takayoshi Ubuka, You Lee Son, George E. Bentley, Lance J. Kriegsfeld
Frontiers in Endocrinology, 6, 179, 179, Frontiers Media SA, 23 Nov. 2015, [Peer-reviewed], [International Magazine]
English, Scientific journal, Since the discovery of gonadotropin-releasing hormone (GnRH) in mammals at the beginning of the 1970s, it was generally accepted that GnRH is the only hypothalamic neuropeptide regulating gonadotropin release in mammals and other vertebrates. In 2000, however, gonadotropin-inhibitory hormone (GnIH), a novel hypothalamic neuropeptide that actively inhibits gonadotropin release, was discovered in quail. Numerous studies over the past decade and a half have demonstrated that GnIH serves as a key player regulating reproduction across vertebrates, acting on the brain and pituitary to modulate reproductive physiology and behavior. In the latter case, recent evidence indicates that GnIH can regulate reproductive behavior through changes in neurosteroid, such as neuroestrogen, biosynthesis in the brain. This review summarizes the discovery of GnIH, and the contributions to GnIH research focused on its mode of action, regulation of biosynthesis, and how these findings advance our understanding of reproductive neuroendocrinology. - A New Pathway Mediating Social Effects on the Endocrine System: Female Presence Acting via Norepinephrine Release Stimulates Gonadotropin-Inhibitory Hormone in the Paraventricular Nucleus and Suppresses Luteinizing Hormone in Quail
Yasuko Tobari, You Lee Son, Takayoshi Ubuka, Yoshihisa Hasegawa, Kazuyoshi Tsutsui
JOURNAL OF NEUROSCIENCE, 34, 29, 9803, 9811, Jul. 2014, [Peer-reviewed]
English, Scientific journal - Evolutionary Origin of GnIH and NPFF in Chordates: Insights from Novel Amphioxus RFamide Peptides
Tomohiro Osugi, Tomoki Okamura, You Lee Son, Makoto Ohkubo, Takayoshi Ubuka, Yasuhisa Henmi, Kazuyoshi Tsutsui
PLoS ONE, 9, 7, e100962, e100962, Public Library of Science (PLoS), 01 Jul. 2014, [Peer-reviewed], [International Magazine]
English, Scientific journal, Gonadotropin-inhibitory hormone (GnIH) is a newly identified hypothalamic neuropeptide that inhibits pituitary hormone secretion in vertebrates. GnIH has an LPXRFamide (X = L or Q) motif at the C-terminal in representative species of gnathostomes. On the other hand, neuropeptide FF (NPFF), a neuropeptide characterized as a pain-modulatory neuropeptide, in vertebrates has a PQRFamide motif similar to the C-terminal of GnIH, suggesting that GnIH and NPFF have diverged from a common ancestor. Because GnIH and NPFF belong to the RFamide peptide family in vertebrates, protochordate RFamide peptides may provide important insights into the evolutionary origin of GnIH and NPFF. In this study, we identified a novel gene encoding RFamide peptides and two genes of their putative receptors in the amphioxus Branchiostoma japonicum. Molecular phylogenetic analysis and synteny analysis indicated that these genes are closely related to the genes of GnIH and NPFF and their receptors of vertebrates. We further identified mature RFamide peptides and their receptors in protochordates. The identified amphioxus RFamide peptides inhibited forskolin induced cAMP signaling in the COS-7 cells with one of the identified amphioxus RFamide peptide receptors expressed. These results indicate that the identified protochordate RFamide peptide gene is a common ancestral form of GnIH and NPFF genes, suggesting that the origin of GnIH and NPFF may date back to the time of the emergence of early chordates. GnIH gene and NPFF gene may have diverged by whole-genome duplication in the course of vertebrate evolution. - Molecular Basis for the Activation of Gonadotropin-Inhibitory Hormone Gene Transcription by Corticosterone
You Lee Son, Takayoshi Ubuka, Misato Narihiro, Yujiro Fukuda, Itaru Hasunuma, Kazutoshi Yamamoto, Denise D. Belsham, Kazuyoshi Tsutsui
ENDOCRINOLOGY, 155, 5, 1817, 1826, May 2014, [Peer-reviewed]
English, Scientific journal - Central and Direct Regulation of Testicular Activity by Gonadotropin-Inhibitory Hormone and Its Receptor
Takayoshi Ubuka, You Lee Son, Yasuko Tobari, Misato Narihiro, George E. Bentley, Lance J. Kriegsfeld, Kazuyoshi Tsutsui
Frontiers in Endocrinology, 5, 8, 8, Frontiers Media SA, 2014, [Peer-reviewed], [International Magazine]
English, Scientific journal, Gonadotropin-inhibitory hormone (GnIH) was first identified in Japanese quail to be an inhibitor of gonadotropin synthesis and release. GnIH peptides have since been identified in all vertebrates, and all share an LPXRFamide (X = L or Q) motif at their C-termini. The receptor for GnIH is the G protein-coupled receptor 147 (GPR147), which inhibits cAMP signaling. Cell bodies of GnIH neurons are located in the paraventricular nucleus (PVN) in birds and the dorsomedial hypothalamic area (DMH) in most mammals. GnIH neurons in the PVN or DMH project to the median eminence to control anterior pituitary function via GPR147 expressed in gonadotropes. Further, GnIH inhibits gonadotropin-releasing hormone (GnRH)-induced gonadotropin subunit gene transcription by inhibiting the adenylate cyclase/cAMP/PKA-dependent ERK pathway in an immortalized mouse gonadotrope cell line (LβT2 cells). GnIH neurons also project to GnRH neurons that express GPR147 in the preoptic area (POA) in birds and mammals. Accordingly, GnIH can inhibit gonadotropin synthesis and release by decreasing the activity of GnRH neurons as well as by directly inhibiting pituitary gonadotrope activity. GnIH and GPR147 can thus centrally suppress testosterone secretion and spermatogenesis by acting in the hypothalamic-pituitary-gonadal axis. GnIH and GPR147 are also expressed in the testis of birds and mammals, possibly acting in an autocrine/paracrine manner to suppress testosterone secretion and spermatogenesis. GnIH expression is also regulated by melatonin, stress, and social environment in birds and mammals. Accordingly, the GnIH-GPR147 system may play a role in transducing physical and social environmental information to regulate optimal testicular activity in birds and mammals. This review discusses central and direct inhibitory effects of GnIH and GPR147 on testosterone secretion and spermatogenesis in birds and mammals. - Molecular Evolution of Kiss2 Genes and Peptides in Vertebrates
You Lee Son
Endocrinology, 154, 11, 4270, 4280, The Endocrine Society, 01 Nov. 2013, [Peer-reviewed]
English, Scientific journal, The kiss1 peptide (kisspeptin), a product of the kiss1 gene, is one of the key neuropeptides regulating vertebrate reproduction. In 2009, we identified a paralogous gene of kiss1 in the brain of amphibians and named it kiss2. Currently, the presence of the kiss2 gene and the kiss2 peptide is still obscure in amniotes compared with that in other vertebrates. Therefore, we performed genome database analyses in primates and reptiles to investigate the molecular evolution of the kiss2 gene in vertebrates. Because the mature kiss2 peptide has been identified only in amphibians, we further performed immunoaffinity purification and mass spectrometry to identify the mature endogenous kiss2 peptide in the brains of salmon and turtle that possessed the kiss2 gene. Here we provide the first evidence for the presence of a kiss2-like gene in the genome database of primates including humans. Synthetic amidated human KISS2 peptide activated human GPR54 expressed in COS7 cells, but nonamidated KISS2 peptide was inactive. The endogenous amidated kiss2 peptide may not be produced in primates because of the lack of an amidation signal in the precursor polypeptide. The kiss2-like gene may be nonfunctional in crocodilians because of premature stop codons. We identified the mature amidated kiss2 peptide in turtles and fish and analyzed the localization of kiss2 peptide mRNA expression in fish. The present study suggests that the kiss2 gene may have mutated in primates and crocodilians and been lost in birds during the course of evolution. In contrast, the kiss2 gene and mature kiss2 peptide are present in turtles and fish. - Gonadotropin-inhibitory hormone (GnIH), GnIH receptor and cell signaling
Takayoshi Ubuka, You Lee Son, George E. Bentley, Robert P. Millar, Kazuyoshi Tsutsui
General and Comparative Endocrinology, 190, 10, 17, Elsevier BV, Sep. 2013, [Peer-reviewed], [International Magazine]
English, Scientific journal, Gonadotropin-inhibitory hormone (GnIH) is an inhibitor of gonadotropin synthesis and release, which was originally identified in the hypothalamus of the Japanese quail (Coturnix japonica). The GnIH precursor polypeptide encodes one GnIH and two GnIH related peptides (GnIH-RP-1 and GnIH-RP-2) in birds that share the same C-terminal LPXRFamide (X=L or Q) motif. The receptor for GnIH is thought to be the G protein-coupled receptor 147 (GPR147) which has been shown to couple predominantly through the Gαi protein to inhibit cAMP production. The crude membrane fraction of COS-7 cells transfected with GPR147 cDNA specifically bound GnIH and GnIH-RPs in a concentration-dependent manner. Scatchard plot analysis of the binding showed that GPR147 possessed a single class of high-affinity binding sites. GnIH neurons project to the median eminence to control anterior pituitary function and GPR147 is expressed in the gonadotropes. GnIH neurons also project to gonadotropin-releasing hormone (GnRH)-I and GnRH-II neurons, and GnRH-I and GnRH-II neurons express GPR147. Thus, GnIH may inhibit gonadotropin synthesis and release by decreasing the activity of GnRH-I neurons as well as directly inhibiting the effects of GnRH on gonadotropes. GnIH may also partially inhibit reproductive behaviors by inhibiting GnRH-II neurons. GnIH and GPR147 are also expressed in the gonads, possibly acting in an autocrine/paracrine manner. The cell signaling process of GPR147 was extensively studied using LβT2 cells, a mouse gonadotrope cell line. In this cell line, mouse GnIH inhibits GnRH-induced gonadotropin subunit, LHβ, FSHβ, and common α, gene transcriptions by inhibiting adenylate cyclase/cAMP/PKA dependent ERK pathway. This review summarizes the functions of GnIH, GnIH receptor and its cell signaling processes in birds and discusses related findings in mammals. - Gonadotropin-Inhibitory Hormone Inhibits GnRH-Induced Gonadotropin Subunit Gene Transcriptions by Inhibiting AC/cAMP/PKA-Dependent ERK Pathway in LβT2 Cells
You Lee Son, Takayoshi Ubuka, Robert P. Millar, Haruhiko Kanasaki, Kazuyoshi Tsutsui
Endocrinology, 153, 5, 2332, 2343, 01 May 2012, [Peer-reviewed]
Scientific journal - 総説:生殖を制御する新規脳ホルモンGnIHの起源と分子進化 比較内分泌学
筒井和義, 大杉知裕, 戸張靖子, 孫 ユリ, 産賀崇由
比較内分泌学, 38, 145, 76, 83, 日本比較内分泌学会, 2012
Japanese - Gonadotropin-inhibitory hormone action in the brain and pituitary
Takayoshi Ubuka, You Lee Son, Yasuko Tobari, Kazuyoshi Tsutsui
Frontiers in Endocrinology, 3, 148, 148, Frontiers Media SA, 2012, [Peer-reviewed], [International Magazine]
English, Scientific journal, Gonadotropin-inhibitory hormone (GnIH) was first identified in the Japanese quail as a hypothalamic neuropeptide inhibitor of gonadotropin secretion. Subsequent studies have shown that GnIH is present in the brains of birds including songbirds, and mammals including humans. The identified avian and mammalian GnIH peptides universally possess an LPXRFamide (X = L or Q) motif at their C-termini. Mammalian GnIH peptides are also designated as RFamide-related peptides from their structures. The receptor for GnIH is the G protein-coupled receptor 147 (GPR147), which is thought to be coupled to G(αi) protein. Cell bodies of GnIH neurons are located in the paraventricular nucleus (PVN) in birds and the dorsomedial hypothalamic area (DMH) in mammals. GnIH neurons in the PVN or DMH project to the median eminence to control anterior pituitary function. GPR147 is expressed in the gonadotropes and GnIH suppresses synthesis and release of gonadotropins. It was further shown in immortalized mouse gonadotrope cell line (LβT2 cells) that GnIH inhibits gonadotropin-releasing hormone (GnRH) induced gonadotropin subunit gene transcriptions by inhibiting adenylate cyclase/cAMP/PKA-dependent ERK pathway. GnIH neurons also project to GnRH neurons in the preoptic area, and GnRH neurons express GPR147 in birds and mammals. Accordingly, GnIH may inhibit gonadotropin synthesis and release by decreasing the activity of GnRH neurons as well as directly acting on the gonadotropes. GnIH also inhibits reproductive behavior possibly by acting within the brain. GnIH expression is regulated by a nocturnal hormone melatonin and stress in birds and mammals. Accordingly, GnIH may play a role in translating environmental information to inhibit reproductive physiology and behavior of birds and mammals. Finally, GnIH has therapeutic potential in the treatment of reproductive cycle and hormone-dependent diseases, such as precocious puberty, endometriosis, uterine fibroids, and prostatic and breast cancers. - General and specific determinants of the selective interactions between SRC-1 NR box-2 and target nuclear receptors
You Lee Son
Molecular Biology Reports, 39, 1, 177, 184, Springer Science and Business Media LLC, Jan. 2012, [Peer-reviewed]
English, Scientific journal - Molecular determinants of the interactions between SRC-1 and LXR/RXR heterodimers
You Lee Son
FEBS Letters, 584, 18, 3862, 3866, Wiley, 24 Sep. 2010, [Peer-reviewed]
English, Scientific journal - Molecular Determinants Required for Selective Interactions between the Thyroid Hormone Receptor Homodimer and the Nuclear Receptor Corepressor N-CoR
You Lee Son
Journal of Molecular Biology, 396, 3, 747, 760, Elsevier BV, Feb. 2010, [Peer-reviewed]
English, Scientific journal - Molecular determinants of the interactions between LXR/RXR heterodimers and TRAP220
You Lee Son
Biochemical and Biophysical Research Communications, 384, 3, 389, 393, Elsevier BV, Jul. 2009, [Peer-reviewed]
English, Scientific journal - Involvement of SMRT Corepressor in Transcriptional Repression by the Vitamin D Receptor
Ji Young Kim, You Lee Son, Young Chul Lee
MOLECULAR ENDOCRINOLOGY, 23, 2, 251, 264, Feb. 2009, [Peer-reviewed]
English, Scientific journal - A role of helix 12 of the vitamin D receptor in SMRT corepressor interaction
You Lee Son
Biochemical and Biophysical Research Communications, Elsevier BV, Feb. 2009, [Peer-reviewed]
English, Scientific journal - RXR heterodimerization allosterically activates LXR binding to the second NR box of activating signal co-integrator-2
You Lee Son, Ok Gu Park, Gwang Sik Kim, Jae Woon Lee, Young Chul Lee
BIOCHEMICAL JOURNAL, 410, 319, 330, Mar. 2008, [Peer-reviewed]
English, Scientific journal
Other Activities and Achievements
- 性腺刺激ホルモン放出抑制ホルモン(GnIH)は甲状腺ホルモンによる生殖制御機構の新たな介在因子である
清原 美佳, 孫 ユリ, 宮田 市郎, 筒井 和義, 日本内分泌学会雑誌, 93, 1, 257, 257, Apr. 2017
(一社)日本内分泌学会, Japanese - 甲状腺ホルモンは性腺刺激ホルモン放出抑制ホルモン(GnIH)の発現を抑制する
清原 美佳, 孫 ユリ, 宮田 市郎, 筒井 和義, 日本内分泌学会雑誌, 92, 1, 259, 259, Apr. 2016
(一社)日本内分泌学会, Japanese - 雌の存在が雄ウズラの生殖内分泌システムを変化させる
戸張靖子, SON You Lee, 産賀崇由, 長谷川喜久, 筒井和義, Annual Meeting of Japanese Avian Endocrinology, 38th, 2014 - 生殖生理と生殖行動を変化させる社会的刺激の脳内機構
戸張靖子, SON You Lee, 産賀崇由, 長谷川喜久, 筒井和義, 日本動物学会大会予稿集, 84th, 2013 - 生殖生理と生殖行動を変化させる社会的刺激受容の神経内分泌機構
戸張靖子, SON You Lee, 産賀崇由, 長谷川喜久, 筒井和義, Annual Meeting of Japanese Avian Endocrinology, 37th, 2013
Research Themes
- 褐色脂肪特異的に発現する細胞表面分子Eva1の機能解析
科学研究費助成事業 基盤研究(C)
01 Apr. 2021 - 31 Mar. 2024
孫 ユリ
体内の余分なエネルギーを蓄積する白色脂肪に対して、褐色脂肪は熱を産生しエネルギー消費を亢進させ肥満を防止する。老化と肥満に伴い褐色脂肪の機能は低下することから、脂肪細胞の褐色化誘導メカニズムは老化や肥満から生じる代謝異常症に対する新たな予防・治療の標的として注目されている。様々な褐色脂肪細胞のマーカー遺伝子が報告されているものの、その機能が明らかになっているのはごく一部しかない。本研究で注目している1回膜貫通型の細胞膜タンパク質であるEpithelial V-like Antigen 1（Eva1、別名；Myelin protein zero-like protein 2、Mpzl2）は、マウスの古典的褐色脂肪細胞の特徴的遺伝子として知られており、ヒトにおいても頚部と副腎周囲の褐色脂肪での発現が確認されているが、脂肪細胞におけるEva1の役割についてはまだ不明である。Eva1は細胞膜タンパク質として同種間の直接的な細胞接着（homophilic interaction）を仲介し、細胞の形態維持や細胞間の相互作用に関わっており、神経膠芽腫幹細胞においては増殖・幹細胞性維持を担っているとの報告があることから、肥満や加齢による脂肪細胞の形態変化および、脂肪幹細胞/前駆細胞の分化能にEva1が関与している可能性が考えられる。そこで本研究では、肥満や老化などによる褐色脂肪細胞の機能低下がEva1発現に及ぼす影響を明らかにし、褐色脂肪細胞におけるEva1発現の制御機構とEva1作用の分子機構の解明に取り組んでいる。
日本学術振興会, 基盤研究(C), 北海道大学, 21K06240 - The potential role of melanopsin in metabolic regulation
Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
01 Apr. 2018 - 31 Mar. 2021
SON YOULEE
The circadian clock has an internally driven 24-hour rhythm. Circadian rhythms generated by central and peripheral clocks maintain homeostasis, including the regulation of metabolic processes. It has been well described that disorders of circadian rhythm promote systemic metabolic dysfunction associated with obesity or diabetes. Melanopsin photopigment expressed in intrinsically photosensitive retinal ganglion cells plays a crucial role in the circadian photoentrainment through the direct projection of melanopsin-expressing cells to the master clock located in the suprachiasmatic nuclei. Thus, disruption of the melanopsin gene impairs circadian photoentrainment, which may lead to metabolic dysfunction. To understand the involvement of melanopsin in metabolic regulation, I examined the phenotype of melanopsin-disrupting mice and measured several risk factors for obesity and metabolic syndrome, such as glucose/insulin tolerance and plasma free fatty acid levels.
Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (C), Keio University, 18K06316 - 甲状腺ホルモンによる生殖制御におけるＧｎＩＨシステムの作用機構
Grants-in-Aid for Scientific Research Grant-in-Aid for JSPS Fellows
24 Apr. 2015 - 31 Mar. 2017
筒井 和義, SON YOU LEE
Thyroid disorders lead to abnormal pubertal development. Although interactions between the thyroid and reproductive endocrine systems are suggested, the detailed mechanisms of how thyroid hormone influences pubertal onset remain unclear. The hypothalamic peptide, gonadotropin-inhibitory hormone (GnIH) was shown to be decreased in the early prepubertal stage, suggesting the possible role of GnIH on pubertal onset. Therefore, we investigated the involvement of GnIH in thyroid status-induced pubertal disorders.
To do this, we induced hypothyroidism and hyperthyroidism in juvenile female mice, then analyzed the change in the regulatory factors of the reproductive axis. Hypothyroidism showed delayed pubertal onset with increased GnIH expression, however hypothyroidism-induced delayed puberty was prevented by GnIH-knockout, suggesting that GnIH may mediate the effect of hypothyroidism on pubertal delay. Reversely, hyperthyroidism had no effect on pubertal onset, however GnIH expression was significantly decreased, indicating the negative correlation between thyroid status and GnIH expression. Further, we found that hypothalamic GnIH neurons express thyroid hormone receptors (TRs), which may convey thyroid hormone signals directly to GnIH neurons. Although TRs did not directly bind to GnIH promoter region, thyroid status actively altered the chromatin modifications in GnIH promoter region.
Our findings indicate a novel function of GnIH to mediate the cross-talk between the hypothalamus-pituitary-thyroid and hypothalamus-pituitary-gonadal axes in proper pubertal development.
Japan Society for the Promotion of Science, Grant-in-Aid for JSPS Fellows, Waseda University, 15F15909 - 時計遺伝子とメラトニンによるGnIH遺伝子の発現制御機構
Grants-in-Aid for Scientific Research Grant-in-Aid for JSPS Fellows
2012 - 2013
SON You Lee
従来の研究により、時計遺伝子やメラトニンが動物の生理状態や行動のリズムを制御することは分かっているが、その分子機構は不明である。本研究は、動物の生殖を制御する重要な新規脳ホルモンであるGnIH (gonadotropin-inhibitory hormlone)に着目して「時計遺伝子とメラトニンによるGnIH遺伝子の発現制御機構」を目的として研究を実施した。
1)時計遺伝子によるGnIH発現の制御機構
1-1)時計遺伝子の一つであるCry1/2の欠損マウス(Cry-nullマウス)でのGnIHの発現が正常マウスと比べて昼の時間帯に著しく増加することを明らかにした。1-2) GnIHニューロンには様々な時計遺伝子が発現していることをラット視床下部由来の細胞株(GnIHニューロン細胞株、rHypoE-23)を用い確認した。1-3) GnIH遺伝子上流に複数存在する時計遺伝子の作用部位であるE-box配列の機能をプロモーターアッセイにより調べた結果、時計遺伝子によるGnIH発現変動は直接E-boxを介した制御機構ではないことが分かった。1-4)体内時計の働きを制御する視交叉上核(SCN)から分泌される血管作動性腸管ペプチド(VIP)の受容体がGnIHニューロンに発現していることを明らかにし、VIPはGnIHニューロン細胞内でcAMP系のシグナルカスケードを活性化させることを明らかにした。
2)メラトニンによるGnIH発現の制御機構
2-1)メラトニン合成能のあるC3Hマウスではメラトニン合成能のないC57BLマウスに比較してGnIHの発現が著しく高いことを明らかにした。2-2) rHypoE-23細胞株にはメラトニン受容体が存在することを明らかにした。2-3)メラトニン受容体のシグナルカスケードの解析するためにrHypoE-23細胞株を用いレポーターアッセイ(CRE, sRE, NFAT-RE)を行った。
Japan Society for the Promotion of Science, Grant-in-Aid for JSPS Fellows, Waseda University, 12F02082
