Role of GABA in the Mechanism of the Onset of Puberty in Non‐Human Primates

Terasawa, Ei

doi:10.1016/s0074-7742(05)71005-9

Cited by 32 publications

(30 citation statements)

References 82 publications

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“…Important drivers of GnRH remodeling are the GABAergic and glutamatergic synaptic inputs (33,34) and so genes involved in these signaling pathways might influence puberty. The strongest candidate gene from our GWAS, NMDAR2B is a glutamate receptor from the NMDA class of receptors.…”

Section: Discussionmentioning

confidence: 99%

Association weight matrix for the genetic dissection of puberty in beef cattle

Fortes

Reverter

Zhang

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

129

148

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We describe a systems biology approach for the genetic dissection of complex traits based on applying gene network theory to the results from genome-wide associations. The associations of singlenucleotide polymorphisms (SNP) that were individually associated with a primary phenotype of interest, age at puberty in our study, were explored across 22 related traits. Genomic regions were surveyed for genes harboring the selected SNP. As a result, an association weight matrix (AWM) was constructed with as many rows as genes and as many columns as traits. Each {i, j} cell value in the AWM corresponds to the z-score normalized additive effect of the ith gene (via its neighboring SNP) on the jth trait. Columnwise, the AWM recovered the genetic correlations estimated via pedigree-based restricted maximum-likelihood methods. Rowwise, a combination of hierarchical clustering, gene network, and pathway analyses identified genetic drivers that would have been missed by standard genome-wide association studies. Finally, the promoter regions of the AWM-predicted targets of three key transcription factors (TFs), estrogen-related receptor γ (ESRRG), Pal3 motif, bound by a PPAR-γ homodimer, IR3 sites (PPARG), and Prophet of Pit 1, PROP paired-like homeobox 1 (PROP1), were surveyed to identify binding sites corresponding to those TFs. Applied to our case, the AWM results recapitulate the known biology of puberty, captured experimentally validated binding sites, and identified candidate genes and genegene interactions for further investigation.bovine | complex traits | fertility | reproduction | systems biology T he analysis of genome-wide association studies (GWASs) applied to complex traits remains a challenge (1). Addressing a complex trait by a single, often binary, phenotypic measure is common practice but is limiting. It is not easy to find the right balance between applying a conservative significance threshold that gives rise to a small number of strong and hopefully biologically meaningful associations and applying a relaxed threshold yielding numerous associations, many of which are new but potentially false. In addition, an increase in sample size coupled with a denser chip results in a larger number of associations that, on average, have a much smaller effect (2). Accepting a large number of associations while simultaneously reducing the number of false positives would be ideal. It is reasonable to propose that a holistic approach applied to a relaxed significance threshold could be the solution. Such a strategy would be particularly useful when investigating the genetic basis of complex traits that, by definition, are influenced by numerous genes and pathways.In our study, age at puberty was the complex phenotype considered. Puberty, or the progression to sexual maturity, is a developmental process with genetic drivers conserved among species (3). It is an important phenotype for the beef industry because late puberty has negative effects on reproduction rates and profitability (4). Age at puberty is moderately heritab...

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Section: Discussionmentioning

confidence: 99%

Association weight matrix for the genetic dissection of puberty in beef cattle

Fortes

Reverter

Zhang

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

129

148

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“…It appeared that the most significantly affected genes were related to gamma aminobutyric acid (GABA) neurotransmission, a finding confirmed using quantitative PCR (qPCR). The involvement was interesting given the developmental reduction in inhibitory GABA control of GnRH secretion that was substantiated in the primate in the period preceding the onset of puberty (22,23) and also shown to occur in the rat using our hypothalamic explant paradigm (24,25).…”

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confidence: 83%

Delayed Neuroendocrine Sexual Maturation in Female Rats After a Very Low Dose of Bisphenol A Through Altered GABAergic Neurotransmission and Opposing Effects of a High Dose

et al. 2016

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Rat sexual maturation is preceded by a reduction of the interpulse interval (IPI) of GnRH neurosecretion. This work aims at studying disruption of that neuroendocrine event in females after early exposure to a very low dose of bisphenol A (BPA), a ubiquitous endocrine disrupting chemical. Female rats were exposed to vehicle or BPA 25 ng/kg·d, 25 μg/kg·d, or 5 mg/kg·d from postnatal day (PND)1 to PND5 or PND15. Exposure to 25 ng/kg·d of BPA for 5 or 15 days was followed by a delay in developmental reduction of GnRH IPI studied ex vivo on PND20. After 15 days of exposure to that low dose of BPA, vaginal opening tended to be delayed. In contrast, exposure to BPA 5 mg/kg·d for 15 days resulted in a premature reduction in GnRH IPI and a trend toward early vaginal opening. RNA sequencing analysis on PND20 indicated that exposure to BPA resulted in opposing dose effects on the mRNA expression of hypothalamic genes involved in gamma aminobutyric acid A (GABAA) neurotransmission. The study of GnRH secretion in vitro in the presence of GABAA receptor agonist/antagonist confirmed an increased or a reduced GABAergic tone after in vivo exposure to the very low or the high dose of BPA, respectively. Overall, we show for the first time that neonatal exposure to BPA leads to opposing dose-dependent effects on the neuroendocrine control of puberty in the female rat. A very low and environmentally relevant dose of BPA delays neuroendocrine maturation related to puberty through increased inhibitory GABAergic neurotransmission.

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“…Notably, GABA transporters play a pivotal role in the regulation of the magnitude and duration of GABA's action (Hu et al, 2004). An increase of GABA transporters' activity at the onset of puberty might decrease GABA concentration in stalk-median eminence (Terasawa, 2005). Not only expressed in mammalian central nervous system, GABA and GABA receptors have also been demonstrated in relatively high concentration in the human ovary, rat ovary, and rat fallopian tube as well as other mammalian reproductive tissues (Martin del Rio and Caballero, 1980;Erdö and László, 1984;Akinci and Schofield, 1999;Biggs et al, 2013;Martyniuk et al, 2013).…”

Section: Ovarian Genes: Differentially Expressed and Interactingmentioning

confidence: 99%

Global differential gene expression in the pituitary gland and the ovaries of pre- and postpubertal Brahman heifers

Nguyen¹,

Reverter²,

Cánovas³

et al. 2017

Journal of Animal Science

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ABSTRACT:To understand genes, pathways, and networks related to puberty, we characterized the transcriptome of two tissues: the pituitary gland and ovaries. Samples were harvested from pre-and postpubertal Brahman heifers (same age group). Brahman heifers (Bos indicus) are older at puberty compared with Bos taurus, a productivity issue. With RNA sequencing, we identified differentially expressed (DEx) genes and important transcription factors (TF) and predicted coexpression networks. The number of DEx genes detected in the pituitary gland was 284 (P < 0.05), and VWC2L was the most DEx gene (fold change = 4.12, P = 0.01). The gene VWC2L promotes bone mineralization through transforming growth factor-β (TGFβ) signaling. Further studies of the link between bone mineralization and puberty could target VWC2L. In ovaries, 3,871 genes were DEx (P < 0.05). Four highly DEx genes were noteworthy for their function: SLC6A13 (a γ-aminobutyric acid [GABA] transporter), OXT (oxytocin), and NPY (neuropeptide Y) and its receptor NPY2R. These genes had higher ovarian expression in postpubertal heifers. The GABA and its receptors and transporters were expressed in the ovaries of many mammals, suggesting a role for this pathway beyond the brain. The OXT pathway has been known to influence the timing of puberty in rats, via modulation of GnRH. The effects of NPY at the hypothalamus, pituitary gland, and ovaries have been documented. Neuropeptide Y and its receptors are known factors in the release of GnRH, similar to OXT and GABA, although their roles in ovarian tissue are less clear. Pathways previously related to puberty such as TGFβ signaling (P = 6.71 × 10 −5 ), Wnt signaling (P = 4.1 × 10 −2 ), and peroxisome proliferator-activated receptor (PPAR) signaling (P = 4.84 × 10 −2 ) were enriched in our data set. Seven genes were identified as key TF in both tissues: HIC2, ZIC4, ZNF219, ZSCAN26, LHX1, OLIG1, and a novel gene. An ovarian subnetwork created with TF and significant ovarian DEx genes revealed five zinc fingers as regulators: ZNF507, ZNF12, ZNF512, ZNF184, and ZNF432. Recent work of hypothalamic gene expression also pointed to zinc fingers as TF for bovine puberty. Although some zinc fingers may be ubiquitously expressed, the identification of DEx genes in common across tissues points to key regulators of puberty. The hypothalamus and pituitary gland had eight DEx genes in common. The hypothalamus and ovaries had 89 DEx genes in common. The pituitary gland and ovaries had 48 DEx genes in common. Our study confirmed the complexity of puberty and suggested further investigation on genes that code zinc fingers.

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Role of GABA in the Mechanism of the Onset of Puberty in Non‐Human Primates

Cited by 32 publications

References 82 publications

Association weight matrix for the genetic dissection of puberty in beef cattle

Association weight matrix for the genetic dissection of puberty in beef cattle

Delayed Neuroendocrine Sexual Maturation in Female Rats After a Very Low Dose of Bisphenol A Through Altered GABAergic Neurotransmission and Opposing Effects of a High Dose

Global differential gene expression in the pituitary gland and the ovaries of pre- and postpubertal Brahman heifers

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