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MAGEL2 is one of the five genes inactivated in Prader-Willi Syndrome (PWS), a genetic disorder, manifesting with symptoms of developmental delay and morbid obesity. Magel2 is highly expressed in the suprachiasmatic nucleus, which is the location of the central clock or circadian pacemaker. Magel2 knockout mice exhibit defects in circadian rhythm. I hypothesized that Magel2 plays a role in one of the inter-connecting feedback loops that control circadian rhythm in suprachiasmatic neurons. I determined that Magel2 acts as a repressive protein in the cycles feedback loop using a luciferase assay. Magel2 exerts this effect by restricting the movement of Bmal1 into the nucleus. Magel2 levels are then reduced by increasing Per2, associated with increase movement into the nucleus, as determined by experiments examining subcellular localization and effects on protein levels. Loss of Magel2 in PWS may contribute to sleep abnormalities in this disorder, specifically the cycling between different sleep stages.

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

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