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      Tanycytes of the Hypothalamic Median Eminence Form a Diet-Responsive Neurogenic Niche

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          Abstract

          Adult hypothalamic neurogenesis has been recently reported, but the cell of origin and function of these newborn neurons are unknown. We utilize genetic fate mapping to show that median eminence tanycytes generate newborn neurons; blocking this neurogenesis alters weight and metabolic activity in adult mice. These findings describe a previously unreported neurogenic niche within the mammalian hypothalamus with important implications for metabolism.

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          Most cited references12

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          Neurogenesis in the hypothalamus of adult mice: potential role in energy balance.

          Ciliary neurotrophic factor (CNTF) induces weight loss in obese rodents and humans, and for reasons that are not understood, its effects persist after the cessation of treatment. Here we demonstrate that centrally administered CNTF induces cell proliferation in feeding centers of the murine hypothalamus. Many of the newborn cells express neuronal markers and show functional phenotypes relevant for energy-balance control, including a capacity for leptin-induced phosphorylation of signal transducer and activator of transcription 3 (STAT3). Coadministration of the mitotic blocker cytosine-beta-d-arabinofuranoside (Ara-C) eliminates the proliferation of neural cells and abrogates the long-term, but not the short-term, effect of CNTF on body weight. These findings link the sustained effect of CNTF on energy balance to hypothalamic neurogenesis and suggest that regulated hypothalamic neurogenesis in adult mice may play a previously unappreciated role in physiology and disease.
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            A genomic atlas of mouse hypothalamic development.

            The hypothalamus is a central regulator of many behaviors that are essential for survival, such as temperature regulation, food intake and circadian rhythms. However, the molecular pathways that mediate hypothalamic development are largely unknown. To identify genes expressed in developing mouse hypothalamus, we performed microarray analysis at 12 different developmental time points. We then conducted developmental in situ hybridization for 1,045 genes that were dynamically expressed over the course of hypothalamic neurogenesis. We identified markers that stably labeled each major hypothalamic nucleus over the entire course of neurogenesis and constructed a detailed molecular atlas of the developing hypothalamus. As a proof of concept of the utility of these data, we used these markers to analyze the phenotype of mice in which Sonic Hedgehog (Shh) was selectively deleted from hypothalamic neuroepithelium and found that Shh is essential for anterior hypothalamic patterning. Our results serve as a resource for functional investigations of hypothalamic development, connectivity, physiology and dysfunction.
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              Hypothalamic tanycytes: a key component of brain-endocrine interaction.

              Tanycytes are bipolar cells bridging the cerebrospinal fluid (CSF) to the portal capillaries and may link the CSF to neuroendocrine events. During the perinatal period a subpopulation of radial glial cells differentiates into tanycytes, a cell lineage sharing some properties with astrocytes and the radial glia, but displaying unique and distinct morphological, molecular, and functional characteristics. Four populations of tanycytes, alpha(1,2) and beta(1,2), can be distinguished. These subtypes express differentially important functional molecules, such as glucose and glutamate transporters; a series of receptors for neuropeptide and peripheral hormones; secretory molecules such as transforming growth factors, prostaglandin E(2), and the specific protein P85; and proteins of the endocytic pathways. This results in functional differences between the four subtypes of tanycytes. Thus, alpha(1,2) tanycytes do not have barrier properties, whereas beta(1,2) tanycytes do. Different types of tanycytes use different mechanisms to internalize and transport cargo molecules; compounds internalized via a clathrin-dependent endocytosis would only enter tanycytes from the CSF. There are also differences in the neuron-tanycyte relationships; beta(1,2) tanycytes are innervated by peptidergic and aminergic neurons, but alpha(1,2) tanycytes are not. Important aspects of the neuron-beta(1) tanycyte relationships have been elucidated. Tanycytes can participate in the release of gonadotropin-releasing hormone (GnRH) to the portal blood by expressing estrogen receptors, absorbing molecules from the CSF, and providing signal(s) to the GnRH neurons. Removal of tanycytes prevents the pulse of GnRH release into the portal blood, the peak of luteinizing hormone, and ovulation. The discovery in tanycytes of new functional molecules is opening a new field of research. Thus, thyroxine deiodinase type II, an enzyme generating triiodothyronine (T(3)) from thyroxine, appears to be exclusively expressed by tanycytes, suggesting that these cells are the main source of brain T(3). Glucose transporter-2 (GLUT-2), a low-affinity transporter of glucose and fructose, and ATP-sensitive K(+) channels are expressed by tanycytes, suggesting that they may sense CSF glucose concentrations.
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                Author and article information

                Journal
                9809671
                21092
                Nat Neurosci
                Nat. Neurosci.
                Nature neuroscience
                1097-6256
                1546-1726
                10 March 2012
                25 March 2012
                01 November 2012
                : 15
                : 5
                : 700-702
                Affiliations
                [1 ]Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA 21287
                [2 ]Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, USA 21287
                [3 ]Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA 21287
                [4 ]Department of Radiation Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA 21287
                [5 ]Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA 21287
                [6 ]Center for High-Throughput Biology, Johns Hopkins University School of Medicine, Baltimore, MD, USA 21287
                [7 ]Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA 21287
                [8 ]Universidad de Antioquia, Medellin, Colombia
                [9 ]Neuroscience Program and the Department of Cell Biology, Smilow Research Center, New York University School of Medicine, New York, NY 10016, USA
                [10 ]Division of Neurobiology and Anatomy, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8510, Japan
                Author notes
                [†]

                These authors contributed equally.

                Article
                NIHMS360926
                10.1038/nn.3079
                3380241
                22446882
                ca5f8fbf-c534-4f8a-a11e-270a87ac6eaf

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                History
                Funding
                Funded by: National Institute of Neurological Disorders and Stroke : NINDS
                Award ID: F31 NS063550-01A2 || NS
                Categories
                Article

                Neurosciences
                Neurosciences

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