Otx2 Induction of the Gonadotropin-releasing Hormone Promoter Is Modulated by Direct Interactions with Grg Co-repressors

Larder, Rachel; Mellon, Pamela L.

doi:10.1074/jbc.m109.002485

Cited by 30 publications

(25 citation statements)

References 74 publications

(68 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Otx2 is expressed in GnRH neurons, where it regulates the expression of GnRH as well as the survival of these neurons [22, 30, 34, 36, 41, 48, 49]. Despite the increased number of cells targeted by the Gnrh-cre allele from as early as e12.5 (see paragraph 5.2), GnRH neuron distribution and the number of GnRH neurons was comparable between Otx2:Lhrh-cre (this study) and Otx2:Gnrh-cre [30].…”

Section: Discussionmentioning

confidence: 99%

“…To compare protein expression patterns between mouse lines, staining was done in parallel with identical conditions. Hypothalamic Gnrh1 content was determined as described previously [19, 34]. The enzymatic LacZ staining was performed by incubating the tissue overnight at 37°C in X-gal staining buffer (1 mg/mL 4-chloro-5-bromo-3-indolyl-β-galactosidase, 5 mM potassium ferrocyanide, 5 mM potassium ferricyanide, and 2 mM MgCl 2 in 100 mM PBS, pH 7.4).…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Differential CRE Expression in Lhrh-cre and GnRH-cre Alleles and the Impact on Fertility in Otx2-Flox Mice

et al. 2019

Self Cite

View full text Add to dashboard Cite

There is an increasing trend in studies utilizing cell-specific deletion of genes through conditional gene deletion by CRE recombination. Despite numerous advantages, this strategy also has limitations such as ectopic CRE-expression and germline recombination. Two commonly used gonadotropin-releasing hormone (Gnrh)-driven CRE-expressing mice both target GnRH neurons. However, a direct comparison of the cells targeted and their phenotypic outcome have not yet been presented. To compare where recombination takes place, we crossed the Gnrh-cre and Lhrh-cre lines with the Rosa26-LacZ reporter mouse. Lhrh-cre allowed recombination of the Rosa26-LacZ gene in ∼700 cells, which is comparable to the GnRH neuronal population. Surprisingly, there were > 20 times more LacZ expressing cells in the adult Gnrh-cre:Rosa26-LacZ than the Lhrh-cre:Rosa26-LacZ brain. The greatest differences in targeting of the Gnrh-cre and Lhrh-cre lines were found in the septum, the suprachiasmatic nucleus, and the septohypothalamic area. This difference in cells targeted was present from embryonic day 12. A prior study using the Gnrh-cre to delete the transcription factor Otx2 found fewer GnRH neurons, leading to male and female subfertility. To recapitulate this study, we performed a fertility assay in Otx2:Lhrh-cre mice. We confirmed the requirement for Otx2 in GnRH neuron development, fertility and correct gonadotropin hormone release in Otx2:Lhrh-cre males, but the subfertility was more modest than in Otx2:Gnrh-cre and absent in female Otx2:Lhrh-cre. This suggests that ectopic expression of Gnrh-cre contributes to the reproductive phenotype observed. Finally, the Cre alleles caused germline recombination of the flox allele when transmitted from either parent, generating embryonic lethal knock-out offspring, producing smaller live litters.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Differential CRE Expression in Lhrh-cre and GnRH-cre Alleles and the Impact on Fertility in Otx2-Flox Mice

et al. 2019

Self Cite

View full text Add to dashboard Cite

show abstract

“…However, as Otx2-null mice are embryonic lethal, due to a failure to develop the forebrain, midbrain and anterior hindbrain, analysis of the development and maintenance of the HPG axis in these mice has not been possible. Recently, Diaczok et al established that deletion of Otx2, specifically from GnRH neurons, results in hypogonadotropic hypogonadism in mice adding in vivo data to previously published reports demonstrating the important role Otx2 plays as a transcriptional regulator of GnRH expression [12-14]. …”

Section: Introductionmentioning

confidence: 98%

Gene dosage of Otx2 is important for fertility in male mice

Larder

Kimura

Meadows

et al. 2013

Molecular and Cellular Endocrinology

Self Cite

View full text Add to dashboard Cite

Together, the hypothalamus, pituitary and gonads direct the development and regulation of reproductive function in mammals. Gonadotropin-releasing hormone (GnRH) expression is limited to ∼800 neurons that originate in the olfactory placode then migrate to the hypothalamus. Coordination of the hypothalamic-pituitary-gonadal (HPG) axis is dependent upon correct neuronal migration of GnRH neurons into the hypothalamus followed by proper synthesis and pulsatile secretion of GnRH. Defects in any one of these processes causes infertility. Otx2, the vertebrate homologue of Drosophila orthodenticle, is a transcription factor that has been shown to be critical for normal brain and eye development and is expressed in both the developing GnRH neurons and the pituitary, suggesting that this gene may play a critical role in development of the HPG axis. As Otx2-null mice are embryonic lethal, we have analyzed the reproductive capacity of heterozygous Otx2 mice to determine the contribution of Otx2 gene dosage to normal HPG axis function. Our data reveal that correct dosage of Otx2 is critical for normal fertility as loss of one allele of Otx2 leads to a discernible reproductive phenotype in male mice due to disruption of the migration of GnRH neurons during development.

show abstract

“…Based on these data, we hypothesize that OTX-2 and its yet unidentified regulatory interacting cofactors are key components in the regulation of GnRH by kisspeptin and may be involved in the process of GnRH activation [53][54][55].…”

Section: Discussionmentioning

confidence: 97%

Kisspeptin Induces Dynamic Chromatin Modifications to Control GnRH Gene Expression

2015

View full text Add to dashboard Cite

In vitro studies have demonstrated an increase in GnRH gene expression associated with an elevated secretory response to kisspeptin administration, suggesting that kisspeptin mediates GnRH expression at both the secretory and pretranslational levels. However, the kisspeptin-mediated intracellular mechanisms associated with the dynamic chromatin modifications modulating GnRH gene expression are unclear. The studies in this manuscript describe specific histone modifications on the enhancer and promoter of the mouse GnRH (mGnRH) gene induced by kisspeptin in GnRH neuronal cell lines (GT1-7 cells). ChIP assays followed by quantitative real-time PCR (qPCR) demonstrate that 15 and 45 min of 10(-9) M kisspeptin significantly increased histone 3 acetylation (H3Ac) at the kisspeptin response element (KsRE) contained between -3446 and -2806 bp of the mGnRH enhancer (GnRHen) in GT1-7 cells, while no changes were observed in the downstream neuron-specific element (NSE). Moreover, kisspeptin specifically induced acetylation of H3AcK14 and K27 and trimethylation of H3 lysine 4 at the KsRE (markers of active chromatin) and no changes in dimethylation of H3K9 (a marker associated with gene repression). Occupancy of RNA Pol II (RNAPII) and a differential carboxyl-terminal domain (CTD) phosphorylation pattern was observed. An interaction between the NSE and the KsRE via a chromatin loop in the mGnRH gene by kisspeptin was detected by the chromosome conformation capture assay (3C). In conclusion, these results demonstrate that kisspeptin induces histone acetylation/methylation and consequently enhances the formation of a chromatin loop in the mGnRH gene which results in known increase in kisspeptin-dependent mGnRH expression.

show abstract

Otx2 Induction of the Gonadotropin-releasing Hormone Promoter Is Modulated by Direct Interactions with Grg Co-repressors

Cited by 30 publications

References 74 publications

Differential CRE Expression in Lhrh-cre and GnRH-cre Alleles and the Impact on Fertility in Otx2-Flox Mice

Differential CRE Expression in Lhrh-cre and GnRH-cre Alleles and the Impact on Fertility in Otx2-Flox Mice

Gene dosage of Otx2 is important for fertility in male mice

Kisspeptin Induces Dynamic Chromatin Modifications to Control GnRH Gene Expression

Contact Info

Product

Resources

About