scholarly journals Targeted Expression of a Dominant-Negative Fibroblast Growth Factor (FGF) Receptor in Gonadotropin-Releasing Hormone (GnRH) Neurons Reduces FGF Responsiveness and the Size of GnRH Neuronal Population

2005 ◽  
Vol 19 (1) ◽  
pp. 225-236 ◽  
Author(s):  
Pei-San Tsai ◽  
Suzanne M. Moenter ◽  
Hector R. Postigo ◽  
Mohammed El Majdoubi ◽  
Toni R. Pak ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Neuronal Cell ◽  
Neuronal Population ◽  
Dominant Negative ◽  
Delayed Puberty ◽  
Fibroblast Growth ◽  
Gnrh Neuron ◽  
Fgf Receptor ◽  
Gnrh Neurons ◽  
A Cell

Abstract Increasing evidence suggests that fibroblast growth factors (FGFs) are neurotrophic in GnRH neurons. However, the extent to which FGFs are involved in establishing a functional GnRH system in the whole organism has not been investigated. In this study, transgenic mice with the expression of a dominant-negative FGF receptor mutant (FGFRm) targeted to GnRH neurons were generated to examine the consequence of disrupted FGF signaling on the formation of the GnRH system. To first test the effectiveness of this strategy, GT1 cells, a GnRH neuronal cell line, were stably transfected with FGFRm. The transfected cells showed attenuated neurite outgrowth, diminished FGF-2 responsiveness in a cell survival assay, and blunted activation of the signaling pathway in response to FGF-2. Transgenic mice expressing FGFRm in a GnRH neuron-specific manner exhibited a 30% reduction in GnRH neuron number, but the anatomical distribution of GnRH neurons was unaltered. Although these mice were initially fertile, they displayed several reproductive defects, including delayed puberty, reduced litter size, and early reproductive senescence. Overall, our results are the first to show, at the level of the organism, that FGFs are one of the important components involved in the formation and maintenance of the GnRH system.

scholarly journals Deletion of the Homeodomain Protein Six6 From GnRH Neurons Decreases GnRH Gene Expression, Resulting in Infertility

Endocrinology ◽  
2019 ◽  
Vol 160 (9) ◽  
pp. 2151-2164 ◽  
Author(s):  
Erica C Pandolfi ◽  
Karen J Tonsfeldt ◽  
Hanne M Hoffmann ◽  
Pamela L Mellon
Keyword(s):  
Hypogonadotropic Hypogonadism ◽  
Neuronal Cell ◽  
Delayed Puberty ◽  
Homeodomain Protein ◽  
Gnrh Neuron ◽  
Direct Role ◽  
Hpg Axis ◽  
Gnrh Neurons

Abstract Hypothalamic GnRH (luteinizing hormone–releasing hormone) neurons are crucial for the hypothalamic-pituitary-gonadal (HPG) axis, which regulates mammalian fertility. Insufficient GnRH disrupts the HPG axis and is often associated with the genetic condition idiopathic hypogonadotropic hypogonadism (IHH). The homeodomain protein sine oculis–related homeobox 6 (Six6) is required for the development of GnRH neurons. Although it is known that Six6 is specifically expressed within a more mature GnRH neuronal cell line and that overexpression of Six6 induces GnRH transcription in these cells, the direct role of Six6 within the GnRH neuron in vivo is unknown. Here we find that global Six6 knockout (KO) embryos show apoptosis of GnRH neurons beginning at embryonic day 14.5 with 90% loss of GnRH neurons by postnatal day 1. We sought to determine whether the hypogonadism and infertility reported in the Six6KO mice are generated via actions within the GnRH neuron in vivo by creating a Six6-flox mouse and crossing it with the LHRHcre mouse. Loss of Six6 specifically within the GnRH neuron abolished GnRH expression in ∼0% of GnRH neurons. We further demonstrated that deletion of Six6 only within the GnRH neuron leads to infertility, hypogonadism, hypogonadotropism, and delayed puberty. We conclude that Six6 plays distinct roles in maintaining fertility in the GnRH neuron vs in the migratory environment of the GnRH neuron by maintaining expression of GnRH and survival of GnRH neurons, respectively. These results increase knowledge of the role of Six6 in the brain and may offer insight into the mechanism of IHH.

Induction of the mesendoderm in the zebrafish germ ring by yolk cell-derived TGF-beta family signals and discrimination of mesoderm and endoderm by FGF

Development ◽  
1999 ◽  
Vol 126 (14) ◽  
pp. 3067-3078 ◽  
Author(s):  
A. Rodaway ◽  
H. Takeda ◽  
S. Koshida ◽  
J. Broadbent ◽  
B. Price ◽  
...  
Keyword(s):  
Ectopic Expression ◽  
Dominant Negative ◽  
Fibroblast Growth ◽  
Tgf Beta ◽  
Fgf Receptor ◽  
Activin Receptor ◽  
Yolk Cell ◽  
Endogenous Expression ◽  
Vertebrate Embryo ◽  
Fgf Signalling

The endoderm forms the gut and associated organs, and develops from a layer of cells which emerges during gastrula stages in the vertebrate embryo. In comparison to mesoderm and ectoderm, little is known about the signals which induce the endoderm. The origin of the endoderm is intimately linked with that of mesoderm, both by their position in the embryo, and by the molecules that can induce them. We characterised a gene, zebrafish gata5, which is expressed in the endoderm from blastula stages and show that its transcription is induced by signals originating from the yolk cell. These signals also induce the mesoderm-expressed transcription factor no tail (ntl), whose initial expression coincides with gata5 in the cells closest to the blastoderm margin, then spreads to encompass the germ ring. We have characterised the induction of these genes and show that ectopic expression of activin induces gata5 and ntl in a pattern which mimics the endogenous expression, while expression of a dominant negative activin receptor abolishes ntl and gata5 expression. Injection of RNA encoding a constitutively active activin receptor leads to ectopic expression of gata5 and ntl. gata5 is activated cell-autonomously, whereas ntl is induced in cells distant from those which have received the RNA, showing that although expression of both genes is induced by a TGF-beta signal, expression of ntl then spreads by a relay mechanism. Expression of a fibroblast growth factor (eFGF) or a dominant negatively acting FGF receptor shows that ntl but not gata5 is regulated by FGF signalling, implying that this may be the relay signal leading to the spread of ntl expression. In embryos lacking both squint and cyclops, members of the nodal group of TGF-beta related molecules, gata5 expression in the blastoderm is abolished, making these factors primary candidates for the endogenous TGF-beta signal inducing gata5.

scholarly journals Activin-mediated mesoderm induction requires FGF

Development ◽  
1994 ◽  
Vol 120 (2) ◽  
pp. 453-462 ◽  
Author(s):  
R.A. Cornell ◽  
D. Kimelman
Keyword(s):  
Dominant Negative ◽  
Mesoderm Induction ◽  
Fibroblast Growth ◽  
Fgf Signaling ◽  
Tgf Beta ◽  
Fgf Receptor ◽  
Basic Fgf ◽  
Dominant Negative Form ◽  
Negative Form

The early patterning of mesoderm in the Xenopus embryo requires signals from several intercellular factors, including mesoderm-inducing agents that belong to the fibroblast growth factor (FGF) and TGF-beta families. In animal hemisphere explants (animal caps), basic FGF and the TGF-beta family member activin are capable of converting pre-ectodermal cells to a mesodermal fate, although activin is much more effective at inducing dorsal and anterior mesoderm than is basic FGF. Using a dominant-negative form of the Xenopus type 1 FGF receptor, we show that an FGF signal is required for the full induction of mesoderm by activin. Animal caps isolated from embryos that have been injected with the truncated FGF receptor and cultured with activin do not extend and the induction of some genes, including cardiac actin and Xbra, is greatly diminished, while the induction of other genes, including the head organizer-specific genes gsc and Xlim-1, is less sensitive. These results are consistent with the phenotype of the truncated FGF receptor-injected embryo and imply that the activin induction of mesoderm depends on FGF, with some genes requiring a higher level of FGF signaling than others.

FGF suppresses apoptosis and induces differentiation of fibre cells in the mouse lens

Development ◽  
1995 ◽  
Vol 121 (12) ◽  
pp. 4383-4393 ◽  
Author(s):  
R.L. Chow ◽  
G.D. Roux ◽  
M. Roghani ◽  
M.A. Palmer ◽  
D.B. Rifkin ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transgenic Mice ◽  
Dominant Negative ◽  
Fgf Receptor ◽  
Fibre Cell ◽  
Dominant Negative Form ◽  
Lens Fibre ◽  
Mouse Lens ◽  
Negative Form

To determine whether fibroblast growth factor (FGF) has a role in lens development, we have generated transgenic mice expressing a dominant-negative form of the murine FGF receptor-1 (FGFRDN) in the lens. Using the fibre cell-specific alpha A-crystallin promoter to express the FGFRDN, we have asked whether FGF is required for fibre cell differentiation. The transgenic mice display diminished differentiation of fibre cells as indicated by their reduced elongation. In addition, transgenic lenses have an unusual refractile anomaly that morphological and biochemical data show results from the apoptosis of fibre cells in the central region of the lens. These results show that lens fibre cells are dependent on FGF for their survival and differentiation, and demonstrate that growth factor deprivation in vivo can lead to apoptosis.

scholarly journals Spatial response to fibroblast growth factor signalling in Xenopus embryos

Development ◽  
1999 ◽  
Vol 126 (1) ◽  
pp. 119-125 ◽  
Author(s):  
B. Christen ◽  
J.M. Slack
Keyword(s):  
Growth Factors ◽  
Source Region ◽  
Dominant Negative ◽  
Fibroblast Growth ◽  
Fgf Receptor ◽  
Erk Activation ◽  
Activation Domains ◽  
Stage Of Development ◽  
Fgf Signalling

We have examined the spatial pattern of activation of the extracellular signal-regulated protein kinase (ERK) during Xenopus development, and show that it closely resembles the expression of various fibroblast growth factors (FGFs). Until the tailbud stage of development, all ERK activation domains are sensitive to the dominant negative FGF receptor, showing that activation is generated by endogenous FGF signalling. ERK is not activated by application of other growth factors like BMP4 or activin, nor is endogenous activation blocked by the respective dominant negative receptors. This shows that various domains of FGF expression, including the periblastoporal region and the midbrain-hindbrain boundary, are also sites of FGF signalling in vivo. Wounding induces a transient (<60 minutes) activation of ERK which is not significantly reduced by the dominant negative FGF receptor. An artificial FGF source, created by injection of eFGF mRNA into cleavage stage embryos, provokes ERK activation outside of its injection site over a range of several cell diameters. The range and extent of ERK activation outside the source region is unchanged by co-injection of a dominant negative form of Ras, which blocks ERK-activation within the source. This suggests that FGF protein can diffuse over several cell diameters.

scholarly journals Gonadotropin-Releasing Hormone Neuron Requirements for Puberty, Ovulation, and Fertility

Endocrinology ◽  
2007 ◽  
Vol 149 (2) ◽  
pp. 597-604 ◽  
Author(s):  
Allan E. Herbison ◽  
Robert Porteous ◽  
Jean-Rémi Pape ◽  
Jocelyn M. Mora ◽  
Peter R. Hurst
Keyword(s):  
Great Majority ◽  
Neuronal Population ◽  
The Body ◽  
Gnrh Neuron ◽  
Neuron Population ◽  
Gonadotropin Secretion ◽  
Estrous Cycles ◽  
Absolute Requirement ◽  
Gnrh Neurons ◽  
Puberty Onset

The absolute requirement for reproduction implies that the hypothalamo-pituitary-gonadal axis, controlling fertility, is an evolutionary robust mechanism. The GnRH neurons of the hypothalamus represent the key cell type within the body dictating fertility. However, the level of functional redundancy within the GnRH neuron population is unknown. As a result of a fortuitous transgene insertion event, GNR23 mice exhibit a marked allele-dependent reduction in GnRH neuron number within their brain. Wild-type mice have approximately 600 GnRH neurons, compared with approximately 200 (34%) and approximately 70 (12%) in GNR23+/− and GNR23−/− mice, respectively. Using these mice, we examined the minimal GnRH neuron requirements for fertility. Male GNR23−/− mice exhibited normal fertility. In contrast, female GNR23−/− mice were markedly subfertile, failing to produce normal litters, have estrous cycles, or ovulate. The failure of ovulation resulted from an inability of the few existing GnRH neurons to generate the LH surge. This was not the case, however, for the first cycle at puberty that appeared normal. Together, these observations demonstrate that 12% of the GnRH neuron population is sufficient for pulsatile gonadotropin secretion and puberty onset, whereas between 12 and 34% are required for cyclical control in adult female mice. This indicates that substantial redundancy exists within the GnRH neuronal population and suggests that the great majority of GnRH neurons must be dysfunctional before fertility is affected.

Neural and Angiogenic Defects in Eyes of Transgenic Mice Expressing a Dominant-Negative FGF Receptor in the Pigmented Cells

2000 ◽  
Vol 71 (4) ◽  
pp. 395-404 ◽  
Author(s):  
Benoı̂t Rousseau ◽  
David Dubayle ◽  
Florian Sennlaub ◽  
Jean-Claude Jeanny ◽  
Pierre Costet ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Dominant Negative ◽  
Fgf Receptor

scholarly journals Anti-Müllerian Hormone, Growth Hormone, and Insulin-Like Growth Factor 1 Modulate the Migratory and Secretory Patterns of GnRH Neurons

2021 ◽  
Vol 22 (5) ◽  
pp. 2445
Author(s):  
Rossella Cannarella ◽  
Alyssa J.J. Paganoni ◽  
Stefania Cicolari ◽  
Roberto Oleari ◽  
Rosita A. Condorelli ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Growth Factor ◽  
Cell Line ◽  
Hypogonadotropic Hypogonadism ◽  
Delayed Puberty ◽  
Insulin Like Growth Factor ◽  
Gnrh Neuron ◽  
Neuron Migration ◽  
Gnrh Secretion ◽  
Gnrh Neurons

Anti-Müllerian hormone (AMH) is secreted by Sertoli or granulosa cells. Recent evidence suggests that AMH may play a role in the pathogenesis of hypogonadotropic hypogonadism (HH) and that its serum levels could help to discriminate HH from delayed puberty. Moreover, the growth hormone (GH)/insulin-like growth factor 1 (IGF1) system may be involved in the function of gonadotropin-releasing hormone (GnRH) neurons, as delayed puberty is commonly found in patients with GH deficiency (GHD) or with Laron syndrome, a genetic form of GH resistance. The comprehension of the stimuli enhancing the migration and secretory activity of GnRH neurons might shed light on the causes of delay of puberty or HH. With these premises, we aimed to better clarify the role of the AMH, GH, and IGF1 on GnRH neuron migration and GnRH secretion, by taking advantage of previously established models of immature (GN11 cell line) and mature (GT1-7 cell line) GnRH neurons. Expression of Amhr, Ghr, and Igf1r genes was confirmed in both cell lines. Cells were then incubated with increasing concentrations of AMH (1.5–150 ng/mL), GH (3–1000 ng/mL), or IGF1 (1.5–150 ng/mL). All hormones were able to support GN11 cell chemomigration. AMH, GH, and IGF1 significantly stimulated GnRH secretion by GT1-7 cells after a 90-min incubation. To the best of our knowledge, this is the first study investigating the direct effects of GH and IGF1 in GnRH neuron migration and of GH in the GnRH secreting pattern. Taken together with previous basic and clinical studies, these findings may provide explanatory mechanisms for data, suggesting that AMH and the GH-IGF1 system play a role in HH or the onset of puberty.

Calcium receptor stimulates chemotaxis and secretion of MCP-1 in GnRH neurons in vitro: potential impact on reduced GnRH neuron population in CaR-null mice

2007 ◽  
Vol 292 (2) ◽  
pp. E523-E532 ◽  
Author(s):  
Naibedya Chattopadhyay ◽  
Kyeong-Hoon Jeong ◽  
Shozo Yano ◽  
Su Huang ◽  
Jian L. Pang ◽  
...  
Keyword(s):  
Cell Lines ◽  
Neuronal Cell ◽  
Neutralizing Antibody ◽  
Cell Types ◽  
Dominant Negative ◽  
Biologically Active ◽  
Mrna Levels ◽  
Monocyte Chemoattractant Protein 1 ◽  
Gnrh Neurons

The factors controlling the migration of mammalian gonadotropin-releasing hormone (GnRH) neurons from the nasal placode to the hypothalamus are not well understood. We studied whether the extracellular calcium-sensing receptor (CaR) promotes migration/chemotaxis of GnRH neurons. We demonstrated expression of CaR in GnRH neurons in the murine basal forebrain and in two GnRH neuronal cell lines: GT1-7 (hypothalamus derived) and GN11 (olfactory bulb derived). Elevated extracellular Ca2+concentrations promoted chemotaxis of both cell types, with a greater effect in GN11 cells. This effect was CaR mediated, as, in both cell types, overexpression of a dominant-negative CaR attenuated high Ca2+-stimulated chemotaxis. We also demonstrated expression of a β-chemokine, monocyte chemoattractant protein-1 (MCP-1), and its receptor, CC motif receptor-2 (CCR2), in the hypothalamic GnRH neurons as well as in GT1-7 and GN11 cells. Exogenous MCP-1 stimulated chemotaxis of both cell lines in a dose-dependent fashion; the effect was greater in GN11 than in GT1-7 cells, consistent with the higher CCR2 mRNA levels in GN11 cells. Activating the CaR stimulated MCP-1 secretion in GT1-7 but not in GN11 cells. MCP-1 secreted in response to CaR stimulation is biologically active, as conditioned medium from GT1-7 cells treated with high Ca2+promoted chemotaxis of GN11 cells, and this effect was partially attenuated by a neutralizing antibody to MCP-1. Finally, in the preoptic area of anterior hypothalamus, the number of GnRH neurons was ∼27% lower in CaR-null mice than in mice expressing the CaR gene. We conclude that the CaR may be a novel regulator of GnRH neuronal migration likely involving, in part, MCP-1.

scholarly journals The Differential Roles for Neurodevelopmental and Neuroendocrine Genes in Shaping GnRH Neuron Physiology and Deficiency

2021 ◽  
Vol 22 (17) ◽  
pp. 9425
Author(s):  
Roberto Oleari ◽  
Valentina Massa ◽  
Anna Cariboni ◽  
Antonella Lettieri
Keyword(s):  
Phenotypic Variability ◽  
Hypogonadotropic Hypogonadism ◽  
Neuroendocrine Cells ◽  
Delayed Puberty ◽  
Neuronal System ◽  
Gnrh Neuron ◽  
Neuron Development ◽  
Gnrh Neurons ◽  
Genes Encoding ◽  
Functional Relevance

Gonadotropin releasing hormone (GnRH) neurons are hypothalamic neuroendocrine cells that control sexual reproduction. During embryonic development, GnRH neurons migrate from the nose to the hypothalamus, where they receive inputs from several afferent neurons, following the axonal scaffold patterned by nasal nerves. Each step of GnRH neuron development depends on the orchestrated action of several molecules exerting specific biological functions. Mutations in genes encoding for these essential molecules may cause Congenital Hypogonadotropic Hypogonadism (CHH), a rare disorder characterized by GnRH deficiency, delayed puberty and infertility. Depending on their action in the GnRH neuronal system, CHH causative genes can be divided into neurodevelopmental and neuroendocrine genes. The CHH genetic complexity, combined with multiple inheritance patterns, results in an extreme phenotypic variability of CHH patients. In this review, we aim at providing a comprehensive and updated description of the genes thus far associated with CHH, by dissecting their biological relevance in the GnRH system and their functional relevance underlying CHH pathogenesis.

Sign in / Sign up

Export Citation Format

Share Document