Regulation of GnRH Gene Expression

Hoffmann, Hanne M.; Mellon, Pamela L.

doi:10.1002/9781119233275.ch5

Cited by 5 publications

(8 citation statements)

References 66 publications

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“…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%

“…The role of well-defined transcriptional regulatory regions, which allow specific expression of a peptide to a limited cell population, are well studied for gonadotropin-releasing hormone (GnRH or LHRH) [13-18], a neuropeptide required for pubertal onset and fertility [11, 19-22]. Despite the careful characterization of the regulatory region of Gnrh1 , it has proven difficult to create a Cre mouse that recapitulates the onset of GnRH expression and specifically targets this small neuronal population compromised of a little under 1,000 neurons in the adult mouse.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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“…Interestingly, SCN and GnRH neurons share some striking similarities. Both depend on homeodomain transcription factors to develop correctly and both possess endogenous rhythms [36,12,22,37,38]. Major differences between GnRH and SCN neuron development include their timing and migratory patterns.…”

Section: Introductionmentioning

confidence: 99%

The Homeodomain Transcription Factors Vax1 and Six6 Are Required for SCN Development and Function

et al. 2019

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The brain's primary circadian pacemaker, the suprachiasmatic nucleus (SCN), is required to translate day-length and circadian rhythms into neuronal, hormonal, and behavioral rhythms. Here, we identify the homeodomain transcription factor Ventral anterior homeobox 1 (Vax1) as required for SCN development, vasoactive intestinal peptide expression, and SCN output. Previous work has shown that VAX1 is required for gonadotropin-releasing hormone (GnRH/LHRH) neuron development, a neuronal population controlling reproductive status. Surprisingly, the ectopic expression of a Gnrh-Cre-allele (Gnrh cre ) in the SCN confirmed the requirement of both VAX1 (Vax1 flox/flox :Gnrh cre , Vax1 Gnrh-cre ) and Sine Oculis Homeobox Protein 6 (Six6 flox/flox :Gnrh cre , Six6 Gnrh-cre ) in SCN function in adulthood. To dissociate the role of Vax1 and Six6 in GnRH neuron and SCN function, we used another Gnrh-cre allele that targets GnRH neurons, but not the SCN (Lhrh cre ). Both Six6 Lhrh-cre and Vax1 Lhrh-cre were infertile, and in contrast to Vax1 Gnrh-cre and Six6 Gnrh-cre mice, Six6 Lhrh-cre and Vax1 Lhrh-cre had normal circadian behavior. Unexpectedly,

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“…The onset of puberty is dependent on increase in the GnRH neuronal activity, which, in turn, increases the expression of GnRH1 gene, and secretes GnRH into hypophyseal portal blood in pulses. 67 The exact mechanism triggering the onset of pulsatile GnRH secretion is still not well characterized. 68 However, it has been proposed that the GnRH neuronal activity is controlled by upstream neuronal networks through neurotransmitters and neuromodulators.…”

Section: Molecules That Regulate Gnrh Neuron Activitymentioning

confidence: 99%

“…After translation, prepro-GnRH peptide is produced, which consists of 92 amino acids. 67 Prepro-GnRH is comprised of N-terminal signal peptide, GnRH, cleavage signal and C-terminal GnRH associated peptide (GAP). Prepro-GnRH is converted into pro-GnRH peptide by removing the N-terminal signal peptide.…”

Section: Synthesis and Secretion Of Gnrhmentioning

confidence: 99%

A classification of genes involved in normal and delayed male puberty

Akram¹,

Rizvi²,

Qayyum³

et al. 2022

Asian Journal of Andrology

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Puberty is a pivotal biological process that completes sexual maturation to achieve full reproductive capability. It is a major transformational period of life, whose timing is strongly affected by genetic makeup of the individual, along with various internal and external factors. Although the exact mechanism for initiation of the cascade of molecular events that culminate in puberty is not yet known, the process of pubertal onset involves interaction of numerous complex signaling pathways of hypothalamo-pituitary-testicular (HPT) axis. We developed a classification of the mechanisms involved in male puberty that allowed placing many genes into physiological context. These include (i) hypothalamic development during embryogenesis, (ii) synaptogenesis where gonadotropin releasing hormone (GnRH) neurons form neuronal connections with suprahypothalamic neurons, (iii) maintenance of neuron homeostasis, (iv) regulation of synthesis and secretion of GnRH, (v) appropriate receptors/proteins on neurons governing GnRH production and release, (vi) signaling molecules activated by the receptors, (vii) the synthesis and release of GnRH, (viii) the production and release of gonadotropins, (ix) testicular development, (x) synthesis and release of steroid hormones from testes, and (xi)the action of steroid hormones in downstream effector tissues. Defects in components of this system during embryonic development, childhood/adolescence, or adulthood may disrupt/nullify puberty, leading to long-term male infertility and/or hypogonadism. This review provides a list of 598 genes involved in the development of HPT axis and classified according to this schema. Furthermore, this review identifies a subset of 75 genes for which genetic mutations are reported to delay or disrupt male puberty.

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Regulation of GnRH Gene Expression

Cited by 5 publications

References 66 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

The Homeodomain Transcription Factors Vax1 and Six6 Are Required for SCN Development and Function

A classification of genes involved in normal and delayed male puberty

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