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

Tsai, Pei‐San; Moenter, Suzanne M.; Postigo, Hector R.; Majdoubi, Mohammed El; Pak, Toni R.; Gill, John C.; Paruthiyil, Sreenivasan; Werner, Sabine; Weiner, Richard I.

doi:10.1210/me.2004-0330

Cited by 100 publications

(99 citation statements)

References 45 publications

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“…Qualitatively, GnRH neurons, although in reduced numbers, could be found throughout their normal anatomical distribution (Tsai et al, 2005;Gill and Tsai, 2006), arguing that FGF signaling does not play a role in determining when or where GnRH neurons cease migration. It has recently been shown that FGFR1 knockouts lack GnRH neurons, indicating that FGF signaling affects differentiation rather than migration (Chung et al, 2008).…”

Section: Discussionmentioning

confidence: 96%

“…Several environmental factors, including glutamate (Simonian and Herbison, 2001), GABA (Fueshko et al, 1998;Bless et al, 2000;Heger et al, 2003), and ligands of fibroblast growth factor receptor-1 (FGFR1; Tsai et al, 2005;Gill and Tsai, 2006), have been implicated as playing a role in the migration of GnRH neurons in the basal forebrain. Glutamate signaling by means of the NMDA receptor appears to have role in the final location of GnRH neurons in the forebrain, because treatment with an NMDA receptor antagonist resulted in an approximately 10% increase in the Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Finally, FGFR1 ligands have been implicated in GnRH neuron migration, since mice with a dominant negative FGFR1 (dnFGFR1) have been shown to have reduced numbers of GnRH neurons (Tsai et al, 2005). Qualitatively, GnRH neurons, although in reduced numbers, could be found throughout their normal anatomical distribution (Tsai et al, 2005;Gill and Tsai, 2006), arguing that FGF signaling does not play a role in determining when or where GnRH neurons cease migration.…”

Section: Discussionmentioning

confidence: 99%

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Anatomical location of mature GnRH neurons corresponds with their birthdate in the developing mouse

Jasoni

Porteous

Herbison

2009

Developmental Dynamics

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The gonadotropin-releasing hormone (GnRH) neurons exhibit substantial functional, anatomical, and molecular heterogeneity, which has hampered their thorough examination. This study was undertaken in an effort to understand whether the anatomical distribution of GnRH neurons is related to their developmental history, because such an association may help explain differences within the population. Using bromodeoxyuridine pulse labeling of timed pregnant female mice we labeled dividing cells, including GnRH neuron progenitors in the olfactory placode, throughout the window of GnRH neuron differentiation. Our results indicate that cells that become postmitotic early tend to populate the rostral aspects of the adult GnRH neuron continuum, whereas later-generated cells tend to settle more caudally; an inside-out pattern reminiscent of neocortex. These observations suggest that the timing of differentiation influences the ability of postmitotic GnRH neurons to navigate to their adult location, and hence may be important in determining the ultimate wiring of the adult network. Developmental Dynamics 238:524 -531, 2009.

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Anatomical location of mature GnRH neurons corresponds with their birthdate in the developing mouse

Jasoni

Porteous

Herbison

2009

Developmental Dynamics

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“…22 Furthermore, a 30% decrease in the number of hypothalamic GnRH neurons was observed in mice with dominant negative Fgfr1 2/2 mutations that were targeted to GnRH neurons, 23 and the early emergence of GnRH neurons appeared to be disrupted in Fgfr1 2/2 hypomorphic mice. 24 Therefore, loss-of-function mutations in FGFR1 result in a defect in GnRH neuron migration via the abnormal morphogenesis of the olfactory bulb, while specific gain-offunction mutations in FGFR1 cause craniosynostosis.…”

Section: Fgfr1 and Fgf8mentioning

confidence: 99%

New understandings of the genetic basis of isolated idiopathic central hypogonadism

Bonomi¹,

Libri²,

Guizzardi³

et al. 2011

Asian J Androl

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Idiopathic hypogonadotropic hypogonadism is a rare disease that is characterized by delayed/absent puberty and/or infertility due to an insufficient stimulation of an otherwise normal pituitary-gonadal axis by gonadotrophin-releasing hormone (GnRH) action. Because reduced or normal luteinizing hormone (LH)/follicle-stimulating hormone (FSH) levels may be observed in the affected patients, the term idiopathic central hypogonadism (ICH) appears to be more appropriate. This disease should be distinguished from central hypogonadism that is combined with other pituitary deficiencies. Isolated ICH has a complex pathogenesis and is fivefold more prevalent in males. ICH frequently appears in a sporadic form, but several familial cases have also been reported. This finding, in conjunction with the description of numerous pathogenetic gene variants and the generation of several knockout models, supports the existence of a strong genetic component. ICH may be associated with several morphogenetic abnormalities, which include osmic defects that, with ICH, constitute the cardinal manifestations of Kallmann syndrome (KS). KS accounts for approximately 40% of the total ICH cases and has been generally considered to be a distinct subgroup. However, the description of several pedigrees, which include relatives who are affected either with isolated osmic defects, KS, or normo-osmic ICH (nICH), justifies the emerging idea that ICH is a complex genetic disease that is characterized by variable expressivity and penetrance. In this context, either multiple gene variants or environmental factors and epigenetic modifications may contribute to the variable disease manifestations. We review the genetic mechanisms that are presently known to be involved in ICH pathogenesis and provide a clinical overview of the 227 cases that have been collected by the collaborating centres of the Italian ICH Network. Asian Journal of Andrology (2012) 14, 49-56; doi:10.1038/aja.2011.68; published online 5 December 201

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“…factors). Among them, two growth factor systems, FGF8/FGFR1 and hepatocyte growth factor, are important regulators of GnRH neuron proliferation and migration (Tsai et al, 2005;Giacobini et al, 2007;Falardeau et al, 2008;Chung and Tsai, 2010). The possible involvement of other embryonic growth factors, however, has not been well documented.…”

Section: Discussionmentioning

confidence: 99%

Regulation of Temporal and Spatial Organization of Newborn GnRH Neurons by IGF Signaling in Zebrafish

Onuma¹,

Ding²,

Abraham³

et al. 2011

J. Neurosci.

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When and how newborn neurons are organized to form a functional network in the developing brain remains poorly understood. An attractive model is the gonadotropin-releasing hormone (GnRH) neuron system, master regulator of the reproductive axis. Here we show that blockage of IGF signaling, a central growth-promoting signaling pathway, by the induced expression of a dominant-negative form of IGF1 receptor (IGF1R) or specific IGF1R inhibitors delayed the emergence of GnRH2 neurons in the midbrain and GnRH3 neurons in the olfactory bulb region. Blockage of IGF signaling also resulted in an abnormal appearance of GnRH3 neurons outside of the olfactory bulb region, although it did not change the locations of other olfactory neurons, GnRH2 neurons, or brain patterning. This IGF action is developmental stage-dependent because the blockade of IGF signaling in advanced embryos had no such effect. An application of phosphatidylinositol 3-kinase (PI3K) inhibitors phenocopied the IGF signaling deficient embryos, whereas the MAPK inhibitors had no effect, suggesting that this IGF action is mediated through the PI3K pathway. Real-time in vivo imaging studies revealed that the ectopic GnRH3 neurons emerged at the same time as the normal GnRH3 neurons in IGF-deficient embryos. Further experiments suggest that IGF signaling affects the spatial distribution of newborn GnRH3 neurons by influencing neural crest cell migration and/or differentiation. These results suggest that the IGF-IGF1R-PI3K pathway regulates the precise temporal and spatial organization of GnRH neurons in zebrafish and provides new insights into the regulation of GnRH neuron development.

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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

Cited by 100 publications

References 45 publications

Anatomical location of mature GnRH neurons corresponds with their birthdate in the developing mouse

Anatomical location of mature GnRH neurons corresponds with their birthdate in the developing mouse

New understandings of the genetic basis of isolated idiopathic central hypogonadism

Regulation of Temporal and Spatial Organization of Newborn GnRH Neurons by IGF Signaling in Zebrafish

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