Timing, Lineage, and Mechanism Underlying Development of Arcuate Nucleus Neurons

弓状核神经元发育的时间、谱系和机制

基本信息

批准号：
9326289
负责人：
Matthew J Biehl
金额：
$ 4.9万
依托单位：
UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-16 至 2018-08-15
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9326289
关键词：
Acute Address Affect American Americas Biological Assay Brain Brain region Bromodeoxyuridine Cell Cycle Cell Line Cell Nucleus Cells Chemicals DNA Binding Data Data Analyses Development Disease Embryo Embryonic Development Epidemic Epigenetic Process Equilibrium Fertility Gene Expression Genes Goals Health Homeostasis Human Hyperphagia Hypogonadism Hypothalamic structure Immunohistochemistry In Situ Hybridization In Vitro Individual Infertility Injection of therapeutic agent KISS1 gene Klinefelter&apos s Syndrome Knock-out Link Luciferases Maintenance Mediating Metabolic Molecular Motor Activity Mus Mutation Neuronal Differentiation Neurons Neuropeptides Neurosecretory Systems Notch Signaling Pathway Obesity Output POMC gene Pathway interactions Peptides Phenotype Pro-Opiomelanocortin Process Puberty Quantitative Reverse Transcriptase PCR Reporter Reproduction Role Signal Transduction Structure Structure of nucleus infundibularis hypothalami Transgenic Organisms Ventricular chromatin immunoprecipitation energy balance feeding high risk increased appetite insight interest mouse model neurogenesis neuron development neuropeptide Y notch protein novel overexpression premature progenitor promoter public health relevance relating to nervous system reproductive reproductive development reproductive function trend

Acute Address Affect American Americas Biological Assay Brain Brain region Bromodeoxyuridine Cell Cycle Cell Line Cell Nucleus Cells Chemicals DNA Binding Data Data Analyses Development Disease Embryo Embryonic Development Epidemic Epigenetic Process Equilibrium Fertility Gene Expression Genes Goals Health Homeostasis Human Hyperphagia Hypogonadism Hypothalamic structure Immunohistochemistry In Situ Hybridization In Vitro Individual Infertility Injection of therapeutic agent KISS1 gene Klinefelter&apos s Syndrome Knock-out Link Luciferases Maintenance Mediating Metabolic Molecular Motor Activity Mus Mutation Neuronal Differentiation Neurons Neuropeptides Neurosecretory Systems Notch Signaling Pathway Obesity Output POMC gene Pathway interactions Peptides Phenotype Pro-Opiomelanocortin Process Puberty Quantitative Reverse Transcriptase PCR Reporter Reproduction Role Signal Transduction Structure Structure of nucleus infundibularis hypothalami Transgenic Organisms Ventricular chromatin immunoprecipitation energy balance feeding high risk increased appetite insight interest mouse model neurogenesis neuron development neuropeptide Y notch protein novel overexpression premature progenitor promoter public health relevance relating to nervous system reproductive reproductive development reproductive function trend

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项目摘要

DESCRIPTION (provided by applicant): The acute nucleus (ARC) is a key regulator of metabolic homeostasis in the brain through actions of two key neurons containing the neuropeptides POMC and NPY. Mutations in Pomc are directly linked to obesity caused by hyperphagy and a reduction in locomotor activity. These phenotypes are observed in both mice and humans. Despite the critical importance of POMC containing neurons, little is known about genes and pathways that regulate both formation of these neurons and expression of Pomc. Another subset of neurons found within the ARC are also involved in reproductive function and puberty onset: Kisspeptin neurons. Disruptions in Kisspeptin signaling result in hypergonadotropic hypogonadism and are linked to infertility. Despite some studies of neurogenesis within the ARC, it is still unclear at which stage of embryogenesis development of each neural subtype occurs. There is strong evidence suggesting that POMC and NPY neurons involved in energy homeostasis arise from a common intermediate progenitor. However, whether Kisspeptin neurons are also derived from the same progenitor remains unknown. It has been accepted that the Notch signaling pathway regulates progenitor maintenance and cell fate in the ARC. If Notch signaling is not extinguished, neurogenesis cannot occur within the ARC. In contrast, if Notch signaling is absent, there is a premature burst of Pomc and NPY neuron differentiation at the expense of HVZ progenitors. The molecular pathway that Notch signaling regulates to control this process is unknown. Additionally, since Kisspeptin neurons also reside within the ARC and are presumed to develop from the same progenitor pool, it is plausible that Notch signaling may be involved in development of these neurons as well. The major goals of this proposal are to determine the lineage relationship of different neurons in the ARC and to define the mechanism by with Notch signaling controls ARC cell fate. Utilizing an established BrdU birthdating paradigm in combination with a well-characterized Pomc reporter line, the timetable and lineage of neurons involved in feeding and reproduction found within the ARC will be determined. Using conditional knock-out and transgenic persistent expressor mouse models, the role of the Notch signaling pathway in development of Kisspeptin neurons will begin to be uncovered. A novel in vitro embryonic hypothalamic cell line will allow exploration of the mechanism by with the Notch signaling pathway regulates expression of genes vital to the establishment of neuronal subtypes of the ARC. Results from these studies will define the progression of neurogenesis in this key homeostatic region of the brain and may provide insight into developmental origins of obesity and infertility.

描述（由适用提供）：急性核us（ARC）是大脑中代谢稳态的关键调节剂，它通过含有神经肽POMC和NPY的两个关键神经元的作用。 POMC中的突变与肥胖症直接相关，由肥大和运动活性减少。这些表型在小鼠和人类中均观察到。尽管含有POMC神经元的重要性至关重要，但对调节这些神经元形成和POMC表达的基因和途径知之甚少。在弧内发现的另一部分神经元也参与了生殖功能和青春期发作：Kisspeptin神经元。亲吻肽信号传导的破坏会导致超单性性低位症，并与不育有关。尽管对ARC内的神经发生进行了一些研究，但仍不清楚每个神经元的胚胎发生阶段，但有强有力的证据表明参与能量稳态的POMC和NPY神经元是由常见的中间祖细胞引起的。然而，是否也来自同一祖细胞的亲肽神经元仍然未知。人们已经接受了Notch信号通路可以调节弧线中的祖细胞的维持和细胞命运。如果没有熄灭Notch信号传导，则神经发生在弧内不可能发生。对比，如果缺乏凹口信号，则会以HVZ祖细胞为代价过早的POMC和NPY神经元分化。 Notch信号传导调节以控制此过程的分子途径尚不清楚。此外，由于Kisspeptin神经元也存在于ARC内，并被认为是从同一祖细胞池开发的，因此也可能参与这些神经元的开发，这是合理的。该提案的主要目标是确定弧中不同神经元的谱系关系，并通过Notch信号传导来定义机制，控制电弧细胞命运。将利用已建立的BRDU生育范式与特征良好的POMC报告范围结合使用，将确定在ARC中发现和繁殖涉及的神经元的时间表和谱系。使用有条件的敲除和转基因持久表达式小鼠模型，将开始发现Notch信号通路在Kisspeptin神经元发展中的作用。一种新型的体外胚胎下丘脑细胞系将通过Notch信号通路来探索该机理，调节对建立ARC神经元亚型至关重要的基因的表达。这些研究的结果将定义神经发生在大脑的关键稳态区域中的进展，并可以洞悉肥胖和不育的发育起源。