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.

Public Health Relevance

The arcuate nucleus of the hypothalamus is a central brain structure vital to maintenance of energy homeostasis and reproductive function. Mutations in genes vital to the function of this region result in obesity due to hyperphagia and reduced locomotor activity as well as hypogonadotropic hypogonadism. This study will explore development of these neuroendocrine circuits and provide mechanistic insights to further our understanding of the contribution of aberrant development to obesity and reproductive deficits.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
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Special Emphasis Panel (ZDK1)
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Castle, Arthur
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University of Illinois Urbana-Champaign
Schools of Arts and Sciences
United States
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Biehl, Matthew J; Kaylan, Kerim B; Thompson, Robert J et al. (2018) Cellular fate decisions in the developing female anteroventral periventricular nucleus are regulated by canonical Notch signaling. Dev Biol 442:87-100
Biehl, Matthew Joseph; Raetzman, Lori Therese (2017) Developmental Origins of Hypothalamic Cells Controlling Reproduction. Semin Reprod Med 35:121-129
Biehl, Matthew J; Raetzman, Lori T (2015) Rbpj-? mediated Notch signaling plays a critical role in development of hypothalamic Kisspeptin neurons. Dev Biol 406:235-46