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

• 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
• 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' 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

 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（由申请人提供）：急性核（ARC）是通过含有神经肽POMC和NPY的两个关键神经元的作用实现脑中代谢稳态的关键调节器。Pomc基因的突变与过度吞噬和运动活动减少引起的肥胖直接相关。这些表型在小鼠和人类中都观察到。尽管含有POMC的神经元至关重要，但对调节这些神经元的形成和Pomc表达的基因和途径知之甚少。在ARC内发现的另一个神经元子集也参与生殖功能和青春期开始：Kisspeptin神经元。Kisspeptin信号传导的中断会导致高促性腺激素性性腺功能减退症，并与不孕症有关。尽管有一些关于ARC内神经发生的研究，但仍然不清楚每个神经亚型的胚胎发生发育阶段。有强有力的证据表明，参与能量稳态的POMC和NPY神经元来自共同的中间祖细胞。然而，Kisspeptin神经元是否也来源于相同的祖细胞仍然未知。已经接受Notch信号传导途径调节ARC中的祖细胞维持和细胞命运。如果Notch信号不消失，ARC内就不能发生神经发生。相反，如果Notch信号传导不存在，则以HVZ祖细胞为代价存在Pomc和NPY神经元分化的过早爆发。Notch信号调节以控制该过程的分子途径是未知的。此外，由于Kisspeptin神经元也存在于ARC内，并且推测从相同的祖细胞库发育，因此Notch信号传导也可能参与这些神经元的发育是合理的。本研究的主要目的是确定ARC中不同神经元的谱系关系，并通过Notch信号控制ARC细胞命运来确定其机制。利用已建立的BrdU出生日期范例结合充分表征的Pomc报告细胞系，将确定ARC内发现的参与摄食和生殖的神经元的时间表和谱系。使用条件性敲除和转基因持续表达小鼠模型，Notch信号通路在Kisspeptin神经元发育中的作用将开始被揭示。一种新的体外胚胎下丘脑细胞系将允许探索通过Notch信号通路调节对ARC神经元亚型的建立至关重要的基因表达的机制。这些研究的结果将确定大脑中这个关键的自我平衡区域的神经发生的进展，并可能为肥胖和不育的发育起源提供见解。