BAX-Dependent and BAX-Independent Regulation of Kiss1 Neuron Development in Mice

Semaan, Sheila J.; Murray, Elaine; Poling, Matthew C.; Dhamija, Sangeeta; Forger, Nancy G.; Kauffman, Alexander S.

doi:10.1210/en.2010-0783

Cited by 93 publications

(91 citation statements)

References 65 publications

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“…Supporting this, mice hypomorphic for Fgf 8 exhibited significantly reduced neuroendocrine oxytocin neurons in the paraventricular and supraoptic nuclei [38]. Of further interest, mice null for Bax, a proapoptotic gene, exhibit a modest but significant increase in KiSS-1 neurons in the AVPV/PeV, although the sexually dimorphic prevalence of KiSS-1 neurons in females remained unaltered [39]. Currently we have no direct evidence to suggest FGF signaling deficiency attenuates the apoptotic pathway, but it is certainly one mechanism by which the size of KP neuronal population can be enhanced in the compound hypomorphs.…”

Section: Tata Et Almentioning

confidence: 80%

Fibroblast Growth Factor Signaling Deficiencies Impact Female Reproduction and Kisspeptin Neurons in Mice1

Tata¹,

Chung²,

Brooks³

et al. 2012

Biology of Reproduction

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Fibroblast growth factor (FGF) signaling is essential for the development of the gonadotropin-releasing hormone (GnRH) system. Mice harboring deficiencies in Fgf8 or Fgf receptor 1 (Fgfr1) suffer a significant loss of GnRH neurons, but their reproductive phenotypes have not been examined. This study examined if female mice hypomorphic for Fgf8, Fgfr1, or both (compound hypomorphs) exhibited altered parameters of pubertal onset, estrous cyclicity, and fertility. Further, we examined the number of kisspeptin (KP)-immunoreactive (ir) neurons in the anteroventral periventricular/periventricular nuclei (AVPV/PeV) of these mice to assess if changes in the KP system, which stimulates the GnRH system, could contribute to the reproductive phenotypes. Single hypomorphs (Fgfr1(+/-) or Fgf8(+/-)) had normal timing for vaginal opening (VO) but delayed first estrus. However, after achieving the first estrus, they underwent normal expression of estrous cycles. In contrast, the compound hypomorphs underwent early VO and normal first estrus, but had disorganized estrous cycles that subsequently reduced their fertility. KP immunohistochemistry on Postnatal Day 15, 30, and 60 transgenic female mice revealed that female compound hypomorphs had significantly more KP-ir neurons in the AVPV/PeV compared to their wild-type littermates, suggesting increased KP-ir neurons may drive early VO but could not maintain the cyclic changes in GnRH neuronal activity required for female fertility. Overall, these data suggest that Fgf signaling deficiencies differentially alter the parameters of female pubertal onset and cyclicity. Further, these deficiencies led to changes in the AVPV/PeV KP-ir neurons that may have contributed to the accelerated VO in the compound hypomorphs.

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Section: Tata Et Almentioning

confidence: 80%

Fibroblast Growth Factor Signaling Deficiencies Impact Female Reproduction and Kisspeptin Neurons in Mice1

Tata¹,

Chung²,

Brooks³

et al. 2012

Biology of Reproduction

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“…All experiments were conducted in accordance with the National Institutes of Health Animal Care and Use Guidelines and with approval of the Animal Care and Use Committee of the University of California, San Diego. Experiment 3 used brain sections collected from adult Bax knockout (KO) mice from a previous study (30).…”

Section: Methodsmentioning

confidence: 99%

“…Single-label ISH was performed as previously described (30,(35)(36)(37). Briefly, slide-mounted DMN sections were fixed in 4% paraformaldehyde, pretreated with acetic anhydride, rinsed in 2 ϫ SSC (sodium citrate, sodium chloride), delipidated in chloroform, dehydrated in ethanols, and air dried.…”

Section: Single-label and Double-label Ishmentioning

confidence: 99%

Development, Sex Steroid Regulation, and Phenotypic Characterization of RFamide-Related Peptide (Rfrp) Gene Expression and RFamide Receptors in the Mouse Hypothalamus

et al. 2012

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Arginine-phenylalanine-amide (RFamide)-related peptide 3 (RFRP-3, encoded by the Rfrp gene) is the mammalian ortholog of gonadotropin-inhibiting hormone and can inhibit GnRH neuronal activity and LH release. However, the development and regulation of the RFRP-3 system in both sexes is poorly understood. Using in situ hybridization, we examined changes in Rfrp-expressing neurons in mice of both sexes during development and under different adulthood hormonal milieus. We found no sex differences in Rfrp expression or cell number in adult mice. Interestingly, we identified two interspersed subpopulations of Rfrp cells (high Rfrp-expressing, HE; low Rfrp-expressing, LE), which have unique developmental and steroidal regulation characteristics. The number of LE cells robustly decreases during postnatal development, whereas HE cell number increases significantly before puberty. Using Bax knockout mice, we determined that the dramatic developmental decrease in LE Rfrp cells is not due primarily to BAX-dependent apoptosis. In adults, we found that estradiol and testosterone moderately repress Rfrp expression in both HE and LE cells, whereas the nonaromatizable androgen dihydrotestosterone has no effect. Using double-label in situ hybridization, we determined that approximately 25% of Rfrp neurons coexpress estrogen receptor-α in each sex, whereas Rfrp cells do not readily express androgen receptor in either sex, regardless of hormonal milieu. Lastly, when we looked at RFRP-3 receptors, we detected some coexpression of Gpr147 but no coexpression of Gpr74 in GnRH neurons of both intact and gonadectomized males and females. Thus, RFRP-3 may exert its effects on reproduction either directly, via Gpr147 in a subset of GnRH neurons, and/or indirectly, via upstream regulators of GnRH.

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“…Indeed, the sham-treated Ar KO group had much greater levels of Kiss1, Tac2, and Pdyn mRNA in the ARC than their WT controls. This implies that AR is involved in the development of KNDy neurons in the ARC (40), possibly reflecting the action of AR on apoptosis in the ARC during development (41,42).…”

Section: Figmentioning

confidence: 96%

Regulation of NKB Pathways and Their Roles in the Control of Kiss1 Neurons in the Arcuate Nucleus of the Male Mouse

et al. 2011

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Kisspeptin (Kiss1) and neurokinin B (NKB) (encoded by the Kiss1 and Tac2 genes, respectively) are indispensable for reproduction. In the female of many species, Kiss1 neurons in the arcuate nucleus (ARC) coexpress dynorphin A and NKB. Such cells have been termed Kiss1/NKB/Dynorphin (KNDy) neurons, which are thought to mediate the negative feedback regulation of GnRH/LH secretion by 17β-estradiol. However, we have less knowledge about the molecular physiology and regulation of Kiss1/Kiss1-expressing neurons in the ARC of the male. Our work focused on the adult male mouse, where we sought evidence for coexpression of these neuropeptides in cells in the ARC, assessed the role of Kiss1 neurons in negative feedback regulation of GnRH/LH secretion by testosterone (T), and investigated the action of NKB on KNDy and GnRH neurons. Results showed that 1) the mRNA encoding Kiss1, NKB, and dynorphin are coexpressed in neurons located in the ARC; 2) Kiss1 and dynorphin A mRNA are regulated by T through estrogen and androgen receptor-dependent pathways; 3) senktide, an agonist for the NKB receptor (neurokinin 3 receptor, encoded by Tacr3), stimulates gonadotropin secretion; 4) KNDy neurons express Tacr3, whereas GnRH neurons do not; and 5) senktide activates KNDy neurons but has no discernable effect on GnRH neurons. These observations corroborate the putative role for KNDy neurons in mediating the negative feedback effects of T on GnRH/LH secretion and provide evidence that NKB released from KNDy neurons is part of an auto-feedback loop that generates the pulsatile secretion of Kiss1 and GnRH in the male.

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BAX-Dependent and BAX-Independent Regulation of Kiss1 Neuron Development in Mice

Cited by 93 publications

References 65 publications

Fibroblast Growth Factor Signaling Deficiencies Impact Female Reproduction and Kisspeptin Neurons in Mice1

Fibroblast Growth Factor Signaling Deficiencies Impact Female Reproduction and Kisspeptin Neurons in Mice1

Development, Sex Steroid Regulation, and Phenotypic Characterization of RFamide-Related Peptide (Rfrp) Gene Expression and RFamide Receptors in the Mouse Hypothalamus

Regulation of NKB Pathways and Their Roles in the Control of Kiss1 Neurons in the Arcuate Nucleus of the Male Mouse

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