Mutual interaction of kisspeptin, estrogen and bone morphogenetic protein-4 activity in GnRH regulation by GT1-7 cells.

Published on Dec 5, 2013in Molecular and Cellular Endocrinology3.871
· DOI :10.1016/J.MCE.2013.07.009
Tomohiro Terasaka10
Estimated H-index: 10
(Okayama University),
Fumio Otsuka35
Estimated H-index: 35
(Okayama University)
+ 7 AuthorsHirofumi Makino98
Estimated H-index: 98
(Okayama University)
Reproduction is integrated by interaction of neural and hormonal signals converging on hypothalamic neurons for controlling gonadotropin-releasing hormone (GnRH). Kisspeptin, the peptide product of the kiss1 gene and the endogenous agonist for the GRP54 receptor, plays a key role in the regulation of GnRH secretion. In the present study, we investigated the interaction between kisspeptin, estrogen and BMPs in the regulation of GnRH production by using mouse hypothalamic GT1-7 cells. Treatment with kisspeptin increased GnRH mRNA expression and GnRH protein production in a concentration-dependent manner. The expression levels of kiss1 and GPR54 were not changed by kisspeptin stimulation. Kisspeptin induction of GnRH was suppressed by co-treatment with BMPs, with BMP-4 action being the most potent for suppressing the kisspeptin effect. The expression of kisspeptin receptor, GPR54, was suppressed by BMPs, and this effect was reversed in the presence of kisspeptin. It was also revealed that BMP-induced Smad1/5/8 phosphorylation and Id-1 expression were suppressed and inhibitory Smad6/7 was induced by kisspeptin. In addition, estrogen induced GPR54 expression, while kisspeptin increased the expression levels of ER alpha. and ER beta, suggesting that the actions of estrogen and kisspeptin are mutually enhanced in GT1-7 cells. Moreover, kisspeptin stimulated MAPKs and AKT signaling, and ERK signaling was functionally involved in the kisspeptin-induced GnRH expression. BMP-4 was found to suppress kisspeptin-induced GnRH expression by reducing ERK signaling activity. Collectively, the results indicate that the axis of kisspeptin-induced GnRH production is bi-directionally controlled, being augmented by an interaction between ER alpha/beta and GPR54 signaling and suppressed by BMP-4 action in GT1-7 neuron cells.
📖 Papers frequently viewed together
21 Authors (Tetsuya Ohtaki, ..., Masahiko Fujino)
1,149 Citations
28 Citations
1,185 Citations
#1Fumio Otsuka (Okayama University)H-Index: 35
������������������������������� ������������������������������������������������ ��������������������������������������� � �����������-����� ������ New biological activities of bone morphogenetic proteins (BMPs in the endocrine system have recently been revealed. The BMP system is composed of approximately 30 ligands and preferential combina‑ tions of type I and type II receptors. The BMP system not only induces bone formation but also plays unique tissue‑specific roles in various organs. For ins...
28 CitationsSource
#1Chian Yu Peng (NU: Northwestern University)H-Index: 18
#2Abhishek Mukhopadhyay (Harvard University)H-Index: 7
Last. John A. Kessler (NU: Northwestern University)H-Index: 94
view all 5 authors...
Hypothalamic neural circuits are known to regulate energy homeostasis and feeding behavior, but how these circuits are established during development is not well understood. Here we report that embryonic neural progenitors that express the transcription factor OLIG1 contribute neurons to the ventral hypothalamus including the arcuate nucleus (ARH), a center that regulates feeding behavior. Ablation of bone morphogenetic protein receptor 1a (BMPR1A) in the OLIG1 lineage resulted in hypophagia, hy...
21 CitationsSource
#1Ei Terasawa (UW: University of Wisconsin-Madison)H-Index: 59
#2Brian P. Kenealy (UW: University of Wisconsin-Madison)H-Index: 12
Estradiol plays a pivotal role in the control of GnRH neuronal function, hence female reproduction. A series of recent studies in our laboratory indicate that rapid excitatory actions of estradiol directly modify GnRH neuronal activity in primate GnRH neurons through GPR30 and STX-sensitive receptors. Similar rapid direct actions of estradiol through estrogen receptor beta are also described in mouse GnRH neurons. In this review, we propose two novel hypotheses as a possible physiological role o...
44 CitationsSource
#1Robert L. Goodman (WVU: West Virginia University)H-Index: 46
#2Michael N. Lehman (UM: University of Michigan)H-Index: 67
The discovery that kisspeptin was critical for normal fertility in humans ushered in a new chapter in our understanding of the control of GnRH secretion. In this paper, we will review recent data on the similarities and differences across several mammalian species in the role of kisspeptin in reproductive neuroendocrinology. In all mammals examined to date, there is strong evidence that kisspeptin plays a key role in the onset of puberty and is necessary for both tonic and surge secretion of GnR...
77 CitationsSource
#1Leonor Pinilla (UCO: University of Córdoba (Spain))H-Index: 67
#2Enrique AguilarH-Index: 61
Last. Manuel Tena-SempereH-Index: 86
view all 5 authors...
Procreation is essential for survival of species. Not surprisingly, complex neuronal networks have evolved to mediate the diverse internal and external environmental inputs that regulate reproduction in vertebrates. Ultimately, these regulatory factors impinge, directly or indirectly, on a final common pathway, the neurons producing the gonadotropin-releasing hormone (GnRH), which stimulates pituitary gonadotropin secretion and thereby gonadal function. Compelling evidence, accumulated in the la...
475 CitationsSource
#1Fumio Otsuka (Okayama University)H-Index: 35
#2Naoko Tsukamoto (Okayama University)H-Index: 13
Last. Hirofumi Makino (Okayama University)H-Index: 98
view all 5 authors...
Abstract The existence of a functional bone morphogenetic protein (BMP) system in the pituitary has been recognized. Recent studies have provided evidence that BMPs elicit differential actions in the regulation of prolactin (PRL) and adrenocorticotropin (ACTH) release in lactotropinoma and corticotropinoma cells, respectively. BMPs play a key role in the modulation of somatostatin receptor (SSTR) sensitivity of lactosomatotrope cells in an autocrine/paracrine manner. In addition, SSTR action enh...
16 CitationsSource
#1Masaya Takeda (UCSD: University of California, San Diego)H-Index: 19
#1Masaya Takeda (UCSD: University of California, San Diego)H-Index: 1
Last. Mark A. Lawson (UCSD: University of California, San Diego)H-Index: 25
view all 8 authors...
It is known that bone morphogenetic proteins (BMPs) regulate gonadotropin transcription and production by pituitary gonadotrope cells. However, the role of BMPs in gonadotropin-releasing hormone (GnRH)-induced FSH production remains uncertain. Here, we describe a functional link between BMP-6 and BMP-7 signals and FSH transcriptional activity induced by GnRH using mouse gonadotrope LβT2 cells. In LβT2 cells, BMP-6 and BMP-7 increased mouse FSHβ-promoter activity in a concentration-dependent mann...
14 CitationsSource
#1David Garcia-Galiano (UCO: University of Córdoba (Spain))H-Index: 31
#2Leonor Pinilla (UCO: University of Córdoba (Spain))H-Index: 67
Last. Manuel Tena-Sempere (UCO: University of Córdoba (Spain))H-Index: 86
view all 3 authors...
Kisspeptins, encoded by the Kiss1 gene, and their canonical receptor, GPR54 (also termed Kiss1R), are unanimously recognised as essential regulators of puberty onset and gonadotrophin secretion. These key reproductive functions stem from the capacity of kisspeptins to stimulate gonadotrophin-releasing hormone (GnRH) secretion in the hypothalamus, where discrete populations of Kiss1 neurones have been identified. In rodents, two major groups of hypothalamic Kiss1 neurones exist: one present in th...
104 CitationsSource
#1Karen J. Tonsfeldt (OSU: Oregon State University)H-Index: 9
#2Cheri P. Goodall (OSU: Oregon State University)H-Index: 11
Last. Patrick E. Chappell (OSU: Oregon State University)H-Index: 17
view all 4 authors...
Oestrogen-stimulated preovulatory gonadotrophin surges are temporally regulated in a way that remains not fully understood. Mammalian ovulation requires surges of gonadotrophin-releasing hormone (GnRH), released from specialised neurones in the hypothalamus. Surge regulation is mediated by ovarian oestrogen (17β-oestradiol; E2) feedback-acting as a negative signal until the early afternoon of the pro-oestrous phase, at which point it stimulates robust increases in GnRH release. Multiple lines of...
42 CitationsSource
#1B.P. KenealyH-Index: 1
#1B.P. KenealyH-Index: 1
Last. Ei Terasawa (UW: University of Wisconsin-Madison)H-Index: 59
view all 3 authors...
Abstract Estrogens play a pivotal role in the control of female reproductive function. Recent studies using primate GnRH neurons derived from embryonic nasal placode indicate that 17β-estradiol (E 2 ) causes a rapid stimulatory action. E 2 (1 nM) stimulates firing activity and intracellular calcium ([Ca 2+ ] i ) oscillations of primate GnRH neurons within a few min. E 2 also stimulates GnRH release within 10 min. However, the classical estrogen receptors, ERα and ERβ, do not appear to play a rol...
17 CitationsSource
Cited By31
#1Edouard Mills (Imperial College London)H-Index: 5
#2Lisa Yang (Imperial College London)H-Index: 5
Last. Alexander N Comninos (Imperial College London)H-Index: 23
view all 6 authors...
Reproductive hormones play a crucial role in the growth and maintenance of the mammalian skeleton. Indeed, the biological significance for this hormonal regulation of skeletal homeostasis is best illustrated by common clinical reproductive disorders, such as Primary Ovarian Insufficiency, Hypothalamic Amenorrhea, Congenital Hypogonadotropic Hypogonadism and Early Menopause, which contribute to the clinical burden of low bone mineral density and increased risk for fragility fracture. Emerging evi...
#1Kevin B. Smith (U of O: University of Ottawa)H-Index: 3
#2Emma Murray (U of O: University of Ottawa)H-Index: 5
Last. Nafissa Ismail (U of O: University of Ottawa)H-Index: 16
view all 8 authors...
Abstract Kisspeptin is a neuropeptide responsible for propagating the hypothalamic-pituitary-gonadal (HPG) axis and initiating puberty. Pubertal exposure to an immune challenge causes enduring sexual behavior dysfunction in males and females, but the mechanism underlying this stress-induced sexual dysfunction remains unknown. Previous findings show that stress exposure can downregulate the HPG axis in adult females. However, it is unclear whether stress induced HPG axis suppression is limited to...
Abstract Spermatogenesis is a complex process that leads to the production of male gametes within the testis through the coordination of mitotic, meiotic and differentiation events, under a deep control of endocrine, paracrine and autocrine modulators along the Hypothalamus-pituitary-gonad (HPG) axis. The kisspeptin system plays a fundamental role along the HPG axis as it is the main positive modulator upstream of the hypothalamic neurons that secrete the Gonadotropin Releasing Hormone (GnRH), t...
3 CitationsSource
#1Yoshiteru Kagawa (Tohoku University)H-Index: 11
#2Banlanjo Abdulaziz Umaru (Tohoku University)H-Index: 3
Last. Yuji Owada (Tohoku University)H-Index: 35
view all 12 authors...
Abstract The onset establishment and maintenance of gonadotropin-releasing hormone (GnRH) secretion is an important phenomenon regulating pubertal development and reproduction. GnRH neurons as well as other neurons in the hypothalamus have high-energy demands and require a constant energy supply from their mitochondria machinery to maintain active functioning. However, the involvement of mitochondrial function in GnRH neurons is still unclear. In this study, we examined the role of NADH Dehydrog...
3 CitationsSource
#1Sylvie Dufour (CNRS: Centre national de la recherche scientifique)H-Index: 73
#2Bruno Quérat (Paris Diderot University)H-Index: 17
Last. Karine RousseauH-Index: 23
view all 6 authors...
In human, as in the other mammals, the neuroendocrine control of reproduction is ensured by the brain-pituitary gonadotropic axis. Multiple internal and environmental cues are integrated via brain ...
12 CitationsSource
Early environmental exposure is recognized as a key factor for long-term health based on the Developmental Origins of Health and Disease hypothesis. It considers that early-life nutrition is now being recognized as a major contributor that may permanently program change of organ structure and function toward the development of diseases, in which epigenetic mechanisms are involved. Recent researches indicate early-life environmental factors modulate the microbiome development and the microbiome m...
5 CitationsSource
#1Ilya V. UlasovH-Index: 32
#2Anton V. Borovjagin (UAB: University of Alabama at Birmingham)H-Index: 11
Last. Danny R. Welch (KU: University of Kansas)H-Index: 80
view all 5 authors...
Tumor suppressors are cellular proteins typically expressed in normal (non-cancer) cells that not only regulate such cellular functions as proliferation, migration and adhesion, but can also be secreted into extracellular space and serve as biomarkers for pathological conditions or tumor progression. KISS1, a precursor for several shorter peptides, known as metastin (Kisspeptin-54), Kisspeptin-14, Kisspeptin-13 and Kisspeptin-10, is one of those metastasis suppressor proteins, whose expression i...
9 CitationsSource
Epigenetics describes how both lifestyle and environment may affect human health through the modulation of genome functions and without any change to the DNA nucleotide sequence. The discovery of several epigenetic mechanisms and the possibility to deliver epigenetic marks in cells, gametes, and biological fluids has opened up new perspectives in the prevention, diagnosis, and treatment of human diseases. In this respect, the depth of knowledge of epigenetic mechanisms is fundamental to preservi...
6 CitationsSource
#1Satoshi Fujisawa (Okayama University)H-Index: 3
#2Motoshi Komatsubara (Okayama University)H-Index: 5
Last. Fumio Otsuka (Okayama University)H-Index: 35
view all 8 authors...
Abstract The impact of orexins on anterior pituitary function has yet to be clarified. We studied the effects of orexin A and its interaction with the bone morphogenetic protein (BMP) system on the regulatory role of prolactin synthesis using rat lactotrope GH3 cells expressing BMP-4. Orexin type 1 receptor (OX1R), but not type 2 receptor (OX2R), was predominantly expressed in GH3 cells. Orexin A suppressed forskolin-induced, but not basal, prolactin mRNA expression without reducing cAMP levels....
2 CitationsSource
#1Seungjoon Kim (KNU: Kyungpook National University)H-Index: 14
Chronic and unpredictable stress can disrupt the female reproductive system by suppression for secretion of gonadotrophin-releasing hormone (GnRH) and gonadotrophin, resulted in ovarian malfunction and infertility. In the recent days, kisspeptin has been highly highlighted as a hypothalamic peptide which directly stimulates synthesis and release for GnRH. However, in spite of the key role of kisspeptin in the female reproductive system, little information is still available on the changes of its...
2 CitationsSource