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Targeted Disruption of the Murine Galanin Gene a

Authors

  • DAVID WYNICK,

    Corresponding author
    1. Department of Medicine, Bristol University, Marlborough Street, Bristol BS2 8HW, UK
    2. Imperial School of Science Technology and Medicine, Endocrine Unit, Hammersmith Hospital, DuCane Road, London W12 ONN, UK
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  • CAROLINE J. SMALL,

    1. Imperial School of Science Technology and Medicine, Endocrine Unit, Hammersmith Hospital, DuCane Road, London W12 ONN, UK
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  • STEPHEN R. BLOOM,

    1. Imperial School of Science Technology and Medicine, Endocrine Unit, Hammersmith Hospital, DuCane Road, London W12 ONN, UK
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  • VASSILIS PACHNIS

    1. Developmental Neurobiology, National Institute for Medical Research, The Ridgeway, London NW7 1AA, UK
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  • a

    This work was supported by the MRC and Wellcome Trust.

Address for correspondence: Dr. David Wynick, Department of Medicine, Bristol University, Marlborough Street, Bristol BS2 8HW, UK. Phone, 44 (0)117 9283396; fax, 44 (0)117 9283976, e-mail, wynick@bris.ac.uk

Abstract

Abstract: The 29 amino acid neuropeptide galanin is widely distributed in the nervous and endocrine systems; highest levels of galanin synthesis and storage occur within the hypothalamus in the median eminence, but it is also abundantly expressed in the basal forebrain, the peripheral nervous system, and gut. To further define the role played by galanin in the peripheral nervous and endocrine systems, a mouse strain carrying a loss-of-function germ-line mutation of the galanin locus, engineered by targeted mutagenesis in embryonic stem cells, has been generated. The mutation removes the first five exons containing the entire coding region for the galanin peptide. Germ-line transmission of the disrupted galanin locus has been obtained, and the mutation has been bred to homozygosity on the inbred 12901aHsd background. Phenotypic analysis of mice lacking a functional galanin gene demonstrate that these animals are viable, grow normally, and can reproduce. A marked reduction in both the anterior pituitary prolactin content and in circulating plasma levels of the hormone is evident. Lactation is abolished along with abrogation of the proliferative response of the lactotroph to estrogen. The responses of sensory neurons to injury in the mutants are markedly impaired. Peripheral nerve regeneration is reduced with associated long-term functional deficits. There is a striking reduction in the development of chronic neuropathic pain. These two phenotypic changes may be explained, in part, by the observation that a subset of dorsal root ganglion neurons is lost in the mutant animals, implying a role for galanin as a trophic cell survival factor. These initial findings have important implications for our understanding and potential therapeutic treatment of (a) sensory nerve regeneration and neuropathic pain and (b) disordered pituitary proliferation and the development of prolactinoma.

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