Obesity, reduced fertility, and disrupted cicadian rhythm in mice with a targeted mutation in the Prader-Willi syndrome gene MAGEL2. R. Wevrick¹, S.V. Koslov², J.M. Bischof¹, A.A. Tennese¹, J.W Bogenpohl³, R. van Gelder⁴, E.D. Herzog³, C.L. Stewart². 1) Dept Med. Genetics, Univ Alberta, Edmonton, AB, Canada; 2) Lab. of Cancer and Dev. Biol., NCI, Frederick, MD; 3) Dept of Biology, Wash. Univ, St. Louis, MO; 4) Dept of Ophthalmology and Visual Sciences, Wash. Univ School of Med, St. Louis, MO.
   Prader-Willi syndrome is a complex disorder resulting from the inactivation of paternally expressed, imprinted genes on chromosome 15q11-q13. Findings include neonatal failure to thrive, developmental delay, sleep apneas, pain insensitivity, excessive daytime sleepiness, neuroendocrine abnormalities, hypogonadotrophic hypogonadism, and insatiable appetite leading to morbid obesity, indicative of hypothalamic dysfunction affecting sleep, circadian rhythm, appetite, and fertility. We are examining the effects of loss of PWS genes individually, and have generated mice with targeted mutations of the PWS imprinted candidate genesnecdin and Magel2. We now show that Magel2-null mice recapitulate fundamental aspects of hypothalamic deficiency in PWS. MAGEL2 shares a MAGE protein homology domain with necdin and may, like necdin, promote neuronal migration and differentiation during development.Magel2 is highly expressed the hypothalamus and in a circadian manner in the suprachiasmatic nucleus. Magel2-null mice have reduced total activity and a less coherent circadian rhythm than control littermates, although they do entrain to a light:dark cycle with a normal period, suggesting a defect in circadian output from the suprachiasmatic nucleus. Magel2-null mice weigh less at weaning, have increased weight gain after weaning that is exacerbated by a moderately high-fat diet, and have reduced fertility compared to control. These results strongly implicate loss of MAGEL2 in the hypothalamic deficiency that profoundly affects appetite, sleep, and reproduction in people with PWS. Previous studies in gene-targeted mice have shown that loss of necdin causes defects in neonatal respiration, sympathetic nervous system function, and pain sensitivity. We propose that the combined loss of necdin and MAGEL2 plays a major role in the complex phenotype of PWS.