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The Magel2-null mouse as a model of Prader-Willi Syndrome

  • Author / Creator
    Mercer, Rebecca E
  • Prader-Willi Syndrome (PWS) is a neurodevelopmental disorder that results from the loss of several paternally expressed genes on chromosome 15q11-q13. People with PWS have an array of phenotypes including hypotonia and early failure to thrive, hypogonadism and infertility, growth hormone deficiency and short stature, childhood onset obesity and hyperphagia, and behavioural problems. Many of the features of PWS have been linked to hypothalamic dysfunction, but the contribution of individual genes lost in PWS and their role in hypothalamic development and function are poorly understood. In order to identify the contribution of individual PWS candidate genes to the PWS phenotype, transgenic mouse strains have been developed to examine consequences of gene loss in an animal model system. One of the genes lost in PWS, with very high expression in the hypothalamus is MAGEL2. Early studies of Magel2-null mice have suggested a role for Magel2 in PWS-associated phenotypes, with circadian rhythm defects and reduced activity, as well as growth abnormalities including reduced weight gain prior to weaning, and increased weight gain and obesity as adults. In this thesis I describe subsequent investigations of the Magel2-null mouse, that confirm it as a key model for numerous aspects of PWS, including behavioural, reproductive, and energy balance abnormalities. Magel2-null mice display subtle reductions in volume in discrete brain regions, neurochemical changes including reduced hypothalamic dopamine and serotonin, and behavioural abnormalities suggesting anxiety (Chapter 2). They have pubertal defects, reduced reproductive capacity and early infertility, and v reproductive changes including abnormal estrous cycles, reduced testosterone and olfactory impairments (Chapter 3). Magel2-null mice display leptin resistance prior to their development of obesity, and an absence of leptin-induced activation of pro-opimelanocortin neurons in the arcuate nucleus of the hypothalamus, a group of neurons linked to reductions in food intake and increased energy expenditure (Chapter 4). Taken together with previous findings, this work indicates a role for MAGEL2 in the pathophysiology of PWS. Future work targeting abnormal phenotypes in Magel2-null mice may suggest treatment possibilities for some features of PWS, including obesity.

  • Subjects / Keywords
  • Graduation date
    2012-11
  • Type of Item
    Thesis
  • Degree
    Doctor of Philosophy
  • DOI
    https://doi.org/10.7939/R3CM3M
  • License
    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
  • Language
    English
  • Institution
    University of Alberta
  • Degree level
    Doctoral
  • Department
    • Medical Sciences-Medical Genetics
  • Supervisor / co-supervisor and their department(s)
    • Colmers, William (Pharmacology)
    • Wevrick, Rachel (Medical Genetics)
  • Examining committee members and their departments
    • Yokota, Toshifumi (Medical Genetics)
    • Hughes, Sarah (Medical Genetics)
    • Girgis, Rose (Pediatrics)
    • Michaud, Jacques (Medical Genetics, University of Montreal)