Loss of MAGEL2 in Prader-Willi Syndrome: Lessons from a Mouse Model

Loss of MAGEL2 in Prader-Willi Syndrome: Lessons from a Mouse Model

Rachel Wevrick, Rebecca E. Mercer, Erin M. Kwolek, and Jocelyn M. Bischof

Department of Medical Genetics and Centre for Neuroscience, University of Alberta, Edmonton, Canada.

Common findings in PWS include neonatal hypotonia and failure to thrive, low metabolic rate, disordered sleep, growth hormone deficiency, childhood-onset severe obesity, hypogonadotrophic hypogonadism, and developmental delay. Some of these findings suggest dysfunction of the hypothalamus, the region in the brain that regulates autonomic function and relays signals between the nervous system and the endocrine system. Multiple mouse models with deficiency of one or more PWS candidate genes have partially correlated individual genes with aspects of the PWS phenotype, but these mice can suffer from partial or complete neonatal lethality and runting, complicating postnatal analysis. In particular, the genetic origins of defects in growth, metabolism, behavior, and reproduction have not been elucidated. We generated gene-targeted mice for two key PWS genes, encoding necdin and MAGEL2. These two proteins are part of the MAGE multi-protein family with roles in cell migration, cytoskeletal rearrangement, neurotrophin signaling, differentiation, and apoptosis.

In mice, Magel2 is highly expressed in a circadian fashion in the suprachiasmatic nucleus of the hypothalamus, the circadian rhythm generating center of the brain. Gene-targeted mutation of Magel2 in mice causes altered circadian rhythm output and reduced motor activity. The role of the hypothalamus in the coordinated regulation of appetite and body weight prompted us to examine whether Magel2 is also required for additional hypothalamic functions that are relevant to abnormal growth and metabolism in PWS. We found that Magel2-null mice exhibit neonatal growth retardation and excessive weight gain after weaning. We also note signs of altered metabolism in adult mice, which recapitulate fundamental aspects of the PWS phenotype such as increased fat mass and decreased lean mass. Both male and female mice have reduced reproductive capacity that declines with age. We are now investigating behavior and motor function in the Magel2-null mice, as we have noted deficits in both these areas. We propose that combined loss of necdin and MAGEL2 act in an additive or cooperative manner to cause delayed or abnormal development of the nervous system, leading to altered physiology in individuals with PWS. Magel2-null mice provide an important opportunity to examine the physiological basis for PWS neonatal failure to thrive and post-weaning weight gain, and to understand the relationships among circadian rhythm, feeding behavior, metabolism, and fertility.

This research was supported by the Canadian Diabetes Association, the Natural Sciences and Engineering Research Council of Canada, the Alberta Heritage Foundation for Medical Research, and the Canadian Institutes of Health Research Training Program in Maternal, Fetal and Newborn Health.