Rachel Wevrick ¹, Rebecca E. Mercer¹, Erin M. Kwolek¹, Jocelyn M. Bischof¹, Glen Baker², Matthijs van Eede^{3, 4}, and R. Mark Henkelman^{3, 4} 

Department of Medical Genetics, University of Alberta, Edmonton, Alberta¹, Department of Psychiatry, University of Alberta, Edmonton, Alberta², Hospital for Sick Children, Mouse Imaging Centre and Auditory Science Laboratory, Toronto, Ontario³, University of Toronto, Departments of Medical Biophysics and Molecular & Medical Genetics, Toronto, Ontario⁴

Introduction/Background:  Prader-Willi Syndrome is a complex neurodevelopmental disorder caused by the inactivation of a small set of imprinted genes on chromosome 15q11-q12.  Affected individuals have a high incidence of behavioral and cognitive deficits including global developmental delay and predisposition to psychiatric disorders.  The MAGEL2 gene is normally highly expressed in the hypothalamus, but is inactivated in individuals with PWS. MAGEL2 is a member of the MAGE/necdin family of proteins that have roles in cell cycle, differentiation, and apoptosis.  Loss of Magel2 in mice causes reduced voluntary activity, a circadian rhythm output defect, decreased lean mass, and increased adiposity, findings that partially recapitulate the human PWS phenotype.     

Methods:  To investigate a possible role for loss of MAGEL2 in the behavioral profile of individuals with PWS, we analyzed brain morphology, brain neurochemistry, and behavior in Magel2-null mice. 

Results/Discussion:  Magel2-null mice have normal motor and learning ability but abnormal behavior in novel environments. Brain volume is reduced, particularly in the nucleus accumbens, hippocampus, and amygdala, as measured by quantitative magnetic resonance imaging. We detected abnormalities in the serotonin pathway by neurochemical profiling of specific brain regions from adult mice, including the cortex and hypothalamus.  

Conclusion:  Our findings demonstrate a role for Magel2 in brain development and behavior in mice, and support a role for loss of MAGEL2 in the neurobehavioral profile of PWS.

Edited: 02/09/2012