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Permanent link (DOI): https://doi.org/10.7939/R3371K

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Role of the Prader-Willi syndrome proteins necdin and Magel2 in the nervous system Open Access

Descriptions

Other title
Subject/Keyword
necdin
Prader-Willi syndrome
homeostasis
Magel2
development
transgenic mouse model
autonomic nervous system
hypothalamic-pituitary
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
Tennese, Alysa
Supervisor and department
Wevrick, Rachel (Medical Genetics)
Examining committee member and department
Greer, John (Physiology)
Waskiewicz, Andrew (Biological Sciences)
Sharkey, Keith (Physiology and Pharmacology, University of Calgary)
Hume, Stacey (Medical Genetics)
Department
Medical Sciences - Medical Genetics
Specialization

Date accepted
2010-10-01T18:08:29Z
Graduation date
2010-11
Degree
Doctor of Philosophy
Degree level
Doctoral
Abstract
Prader-Willi syndrome (PWS) is a rare, neurodevelopmental disorder with multiple features caused by hypothalamic deficiency, including infantile failure to thrive, hyperphagia leading to obesity, growth hormone deficiency, hypogonadism, and central adrenal insufficiency. Other features of PWS including global developmental delay, hypotonia, pain insensitivity, gastrointestinal dysfunction, and psychiatric disorders are caused by deficits in other regions of the nervous system. PWS is caused by the loss of a subset of paternally-expressed genes on chromosome 15, which includes NDN and MAGEL2. Necdin and Magel2 are both members of the melanoma antigen (MAGE) family of proteins and are expressed throughout development, particularly in the nervous system. This thesis describes experiments that examine the loss of function of necdin and Magel2 in mice and their potential roles in the pathogenesis of PWS. Targeted inactivation of Ndn and Magel2 in mice has aided in determining how loss of function of these proteins affects the development and function of the nervous system. Loss of necdin causes reduced axonal outgrowth and neuronal differentiation in the central and peripheral sensory nervous systems. I examined the autonomic nervous system in Ndn-null embryos and identified a defect in the migration of the most rostral sympathetic chain ganglion and consequently increased neuronal cell death and reduced innervation of target tissues supplied by this ganglion. Reduced axonal outgrowth was observed throughout the sympathetic nervous system in Ndn-null embryos although no gross deficits in the parasympathetic and enteric nervous systems were identified. Loss of Magel2 causes reduced fertility and abnormal circadian rhythm patterns in mice. I further identified an altered response to stress, a delayed response to insulin-induced hypoglycemia, a reduced stimulated growth hormone response, and lower thyroid hormone levels in Magel2-null mice, indicative of deficits in multiple hypothalamic-pituitary axes. The findings presented in this thesis support a role for necdin and Magel2 in the development and function of the nervous system. The data also indicates that these MAGE proteins play a key role in multiple features of PWS, including endocrine deficiencies and autonomic dysfunction
Language
English
DOI
doi:10.7939/R3371K
Rights
License granted by Alysa Tennese (poulin@ualberta.ca) on 2010-10-01T17:35:47Z (GMT): 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 the above terms. The author reserves all other publication and other rights in association with the copyright in the thesis, and except as herein 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.
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