Neurosecretory Gene Expression in the Hypothalamus
下丘脑的神经分泌基因表达
基本信息
- 批准号:10619540
- 负责人:
- 金额:$ 54.05万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-08-15 至 2025-04-30
- 项目状态:未结题
- 来源:
- 关键词:AddressAdultAnteriorApoptosisArgipressinAxonCell Differentiation processCell LineCellsCircadian RhythmsCuesDefectDevelopmentEmbryoEstrous CycleExhibitsFailureFeedsFertilityFoundationsGene ExpressionGene Expression RegulationGenesGeneticGenetic TranscriptionGoalsGonadal Steroid HormonesGonadotropin Hormone Releasing HormoneHeterozygoteHomeoboxHomeodomain ProteinsHormonesHypothalamic structureIn VitroInfertilityKISS1 geneKnock-outKnockout MiceLaboratoriesMethodologyMolecularMorphologyMusMutationNeuritesNeuroendocrine CellNeuronsNeuropeptidesNeurosecretory SystemsOlfactory NervePathway interactionsPerinatal mortality demographicsPhysiologicalPituitary GlandPopulationPubertyRegulationRegulatory PathwayReproductionRoleSex BehaviorSignal TransductionSmall Interfering RNATestosteroneTransfectionTransgenic OrganismsVIP geneVasoactive Intestinal PeptideVentral Anterior Thalamic Nucleuscircadiancircadian pacemakerexperiencehomeodomainin vitro Modelin vivoinnovationinsightmalemedian eminencemigrationneural circuitneuron developmentneuronal circuitrynovelpromoterreproductivereproductive functionresponsesubfertilitysuprachiasmatic nucleustranscription factor
项目摘要
Project Summary
The neural circuit that controls mammalian reproduction delivers circadian information from the suprachiasmatic
nucleus (SCN) via the neuropeptides arginine vasopressin (AVP) and vasoactive intestinal peptide (VIP) to the
kisspeptin (Kiss) and gonadotropin-releasing hormone (GnRH) neurons, respectively. Infertility can be caused
at the neuroendocrine level by genetic defects in GnRH neurons, Kiss neurons, and/or circadian pacemaker and
neuropeptide neurons in the SCN. GnRH neurons arise in the olfactory placode, migrate into the hypothalamus,
and extend their axons to the median eminence to deliver GnRH to the pituitary in response to Kiss signals.
Disrupted migration, neurite pathfinding, and/or disregulated secretion of Kiss or GnRH neurons result in failures
of puberty, fertility, and reproductive function. We have determined that the homeodomain transcription factors,
Vax1, Six3, and Six6, are all crucial for reproduction. Six6 Knock-out (KO) mice exhibit strikingly decreased
fertility, while heterozygote Vax1 and Six3 mice are subfertile (Vax1 and Six3 KO mice are perinatal lethal).
Though GnRH neuron numbers are normal at e13.5, all three of the KO embryos have ~90% reductions in
hypothalamic GnRH neurons by e17.5. Vax1, Six3, and Six6 are found in Kiss neurons and regulate expression
of the Kiss promoter in Kiss-expressing cell lines. In addition, deletion of Six3 from Kiss neurons causes
subfertility. Furthermore, all three KO e17.5 embryos lack SCN morphology and fail to express AVP and VIP,
and Six6 KO adults lack circadian rhythms. The overall goal of this application is to elucidate the development
of this fundamental reproductive neuroendocrine circuit (SCNKissGnRH) at the molecular, developmental,
and physiological levels. We propose three Specific Aims: Aim 1 will investigate differentiation and maturation
of GnRH neurons during migration by determining the fate of neurons lacking these factors and effects on their
migratory pathway. Aim 2 will focus on the roles of Vax1, Six3, and Six6 in the development and function of Kiss
neurons in vitro and in vivo with a focus on direct regulation of Kiss gene expression and effects on fertility. Aim
3 will address the fundamental mechanisms of SCN development, the contribution of Vax1, Six3, and Six6 to
AVP and VIP gene expression, and investigate the roles of SCN circadian function in fertility. Our overarching
hypothesis is that infertility due to defects in Vax1, Six3, and Six6 is caused by alterations in specific
hypothalamic neuroendocrine cell populations within the hypothalamic SCNKissGnRH reproductive
neurocircuit by regulation of development, hormone synthesis, and circadian rhythms. We believe that studies
of these key homeodomain proteins will reveal fundamental mechanisms in the control of reproductive function
and circadian rhythms and provide valuable insight into novel regulatory pathways important for the development
and function of this neuroendocrine circuit. This multifaceted approach will yield a comprehensive understanding
of their roles in fertility and circadian rhythms in vivo and in vitro, and provide further insight into the fundamental
genetic control of infertility and circadian rhythms.
项目概要
控制哺乳动物繁殖的神经回路从视交叉上传递昼夜节律信息
细胞核(SCN)通过神经肽精氨酸加压素(AVP)和血管活性肠肽(VIP)到达
分别是 Kisspeptin (Kiss) 和促性腺激素释放激素 (GnRH) 神经元。可能会导致不孕不育
在神经内分泌水平上,GnRH 神经元、Kiss 神经元和/或昼夜节律起搏器的遗传缺陷导致
SCN 中的神经肽神经元。 GnRH 神经元出现在嗅板,迁移到下丘脑,
并将它们的轴突延伸到正中隆起,以响应 Kiss 信号将 GnRH 传递到垂体。
迁移中断、神经突寻路和/或 Kiss 或 GnRH 神经元分泌失调会导致失败
青春期、生育力和生殖功能。我们已经确定同源域转录因子,
Vax1、Six3 和 Six6 对于繁殖都至关重要。 Six6 基因敲除 (KO) 小鼠表现出显着下降
生育能力,而杂合子 Vax1 和 Six3 小鼠生育力低下(Vax1 和 Six3 KO 小鼠围产期致死)。
尽管 GnRH 神经元数量在 e13.5 时正常,但所有三个 KO 胚胎的 GnRH 神经元数量均减少了约 90%
e17.5 的下丘脑 GnRH 神经元。 Vax1、Six3 和 Six6 存在于 Kiss 神经元中并调节表达
Kiss表达细胞系中Kiss启动子的作用。此外,从 Kiss 神经元中删除 Six3 会导致
生育能力低下。此外,所有三个 KO e17.5 胚胎都缺乏 SCN 形态并且无法表达 AVP 和 VIP,
Six6 KO 成虫缺乏昼夜节律。该应用程序的总体目标是阐明开发
这个基本的生殖神经内分泌回路(SCNKissGnRH)在分子、发育、
和生理水平。我们提出三个具体目标: 目标 1 将研究分化和成熟
通过确定缺乏这些因子的神经元的命运及其对其的影响,对迁移过程中的 GnRH 神经元进行研究
迁徙途径。 Aim 2 将重点关注 Vax1、Six3 和 Six6 在 Kiss 的开发和功能中的作用
体外和体内神经元的研究,重点是 Kiss 基因表达的直接调节及其对生育力的影响。目的
3 将讨论 SCN 发育的基本机制,Vax1、Six3 和 Six6 对 SCN 发育的贡献
AVP 和 VIP 基因表达,并研究 SCN 昼夜节律功能在生育力中的作用。我们的首要任务
假设 Vax1、Six3 和 Six6 缺陷导致的不孕症是由特定基因的改变引起的
下丘脑 SCN 内的下丘脑神经内分泌细胞群KissGnRH 生殖
通过调节发育、激素合成和昼夜节律来调节神经回路。我们相信,研究
这些关键同源域蛋白的研究将揭示控制生殖功能的基本机制
和昼夜节律,并为对发展重要的新监管途径提供宝贵的见解
以及该神经内分泌回路的功能。这种多方面的方法将产生全面的理解
它们在体内和体外的生育和昼夜节律中的作用,并提供对基本原理的进一步见解
不孕症和昼夜节律的遗传控制。
项目成果
期刊论文数量(7)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
The molecular phenotype of kisspeptin neurons in the medial amygdala of female mice.
- DOI:10.3389/fendo.2023.1093592
- 发表时间:2023
- 期刊:
- 影响因子:5.2
- 作者:
- 通讯作者:
Metabolic actions of kisspeptin signaling: Effects on body weight, energy expenditure, and feeding.
- DOI:10.1016/j.pharmthera.2021.107974
- 发表时间:2022-03
- 期刊:
- 影响因子:13.5
- 作者:Hudson AD;Kauffman AS
- 通讯作者:Kauffman AS
Estrogen Regulation of the Molecular Phenotype and Active Translatome of AVPV Kisspeptin Neurons.
雌激素对 AVPV Kisspeptin 神经元分子表型和活性翻译组的调节。
- DOI:10.1210/endocr/bqab080
- 发表时间:2021
- 期刊:
- 影响因子:4.8
- 作者:Stephens,ShannonBZ;Kauffman,AlexanderS
- 通讯作者:Kauffman,AlexanderS
Neuroendocrine mechanisms underlying estrogen positive feedback and the LH surge.
- DOI:10.3389/fnins.2022.953252
- 发表时间:2022
- 期刊:
- 影响因子:4.3
- 作者:Kauffman, Alexander S.
- 通讯作者:Kauffman, Alexander S.
Developmental sex differences in the peri-pubertal pattern of hypothalamic reproductive gene expression, including Kiss1 and Tac2, may contribute to sex differences in puberty onset.
- DOI:10.1016/j.mce.2022.111654
- 发表时间:2022-07-01
- 期刊:
- 影响因子:4.1
- 作者:Semaan, Sheila J.;Kauffman, Alexander S.
- 通讯作者:Kauffman, Alexander S.
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PAMELA L MELLON其他文献
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{{ truncateString('PAMELA L MELLON', 18)}}的其他基金
Neurosecretory Gene Expression in the Hypothalamus
下丘脑的神经分泌基因表达
- 批准号:
10396658 - 财政年份:2020
- 资助金额:
$ 54.05万 - 项目类别:
Neurosecretory Gene Expression in the Hypothalamus
下丘脑的神经分泌基因表达
- 批准号:
10052992 - 财政年份:2020
- 资助金额:
$ 54.05万 - 项目类别:
Neurosecretory Gene Expression in the Hypothalamus
下丘脑的神经分泌基因表达
- 批准号:
10239241 - 财政年份:2020
- 资助金额:
$ 54.05万 - 项目类别:
Neuroendocrine Actions of Androgens in Female Reproduction
雄激素在女性生殖中的神经内分泌作用
- 批准号:
8809606 - 财政年份:2015
- 资助金额:
$ 54.05万 - 项目类别:
PROJECT 1 - INTEGRATION OF HORMONE SIGNALING IN THE PITUITARY GONADOTROPE
项目 1 - 垂体促性腺激素信号传导的整合
- 批准号:
7683478 - 财政年份:2009
- 资助金额:
$ 54.05万 - 项目类别:
Horomone Control of Gene Expression in the Gonadotrope
激素对促性腺激素基因表达的控制
- 批准号:
7052247 - 财政年份:2005
- 资助金额:
$ 54.05万 - 项目类别:
Endocrine and Growth Factor Regulation in the Pituitary
垂体中的内分泌和生长因子调节
- 批准号:
6918355 - 财政年份:2005
- 资助金额:
$ 54.05万 - 项目类别:
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