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

Descriptions

Other title
Subject/Keyword
Hypothalamus
Magel2-null mice
Prader-Willi Syndrome
Leptin Signaling
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
Mercer, Rebecca E
Supervisor and department
Colmers, William (Pharmacology)
Wevrick, Rachel (Medical Genetics)
Examining committee member and department
Girgis, Rose (Pediatrics)
Michaud, Jacques (Medical Genetics, University of Montreal)
Hughes, Sarah (Medical Genetics)
Yokota, Toshifumi (Medical Genetics)
Department
Medical Sciences-Medical Genetics
Specialization

Date accepted
2012-08-24T15:31:33Z
Graduation date
2012-11
Degree
Doctor of Philosophy
Degree level
Doctoral
Abstract
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.
Language
English
DOI
doi:10.7939/R3CM3M
Rights
Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
Citation for previous publication
Mercer, R.E., Kwolek, E.M., Bischof, J.M., van Eede, M., Henkelman, R.M., and Wevrick, R. (2009) Regionally reduced brain volume, altered serotonin neurochemistry, and abnormal behaviour in mice null for the circadian rhythm output gene Magel2. Am J Med Genet B Neuropsychiatr Genet 150B(8):1085-1099.Mercer, R.E., and Wevrick, R. (2009) Loss of Magel2, a Candidate Gene for Features of Prader-Willi Syndrome, Impairs Reproductive Function in Mice. PLoS One. 4(1):e4291.

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