Abstract
BackgroundThe Magel2 gene is most highly expressed in the suprachiasmatic nucleus of the hypothalamus, where its expression cycles in a circadian pattern comparable to that of clock-controlled genes. Mice lacking the Magel2 gene have hypothalamic dysfunction, including circadian defects that include reduced and fragmented total activity, excessive activity during the subjective day, but they have a normal circadian period. Magel2 is a member of the MAGE family of proteins that have various roles in cellular function, but the specific function of Magel2 is unknown.MethodsWe used a variety of cell-based assays to determine whether Magel2 modifies the properties of core circadian rhythm proteins.ResultsMagel2 represses the activity of the Clock:Bmal1 heterodimer in a Per2-luciferase assay. Magel2 interacts with Bmal1 and with Per2 as measured by co-immunoprecipitation in co-transfected cells, and exhibits a subcellular distribution consistent with these interactions when visualized by immunofluorescence. As well, Magel2 induces the redistribution of the subcellular localization of Clock towards the cytoplasm, in contrast to the nucleus-directed effect of Bmal1 on Clock subcellular localization.ConclusionConsistent with the blunted circadian rhythm observed in Magel2-null mice, these data suggest that Magel2 normally promotes negative feedback regulation of the cellular circadian cycle, through interactions with key core circadian rhythm proteins.
Highlights
Prader-Willi syndrome (PWS) is a genetic neurodevelopmental disorder featuring neonatal failure to thrive, hyperphagia leading to obesity, growth hormone deficiency, and other findings [1,2,3]
Using running wheel activity monitoring, we previously found that gene-targeted Magel2-deficient mice had reduced and more fragmented total activity, with a diminished circadian amplitude [7]
Expression of Magel2 reduces Clock:Bmal1 heterodimer activity at the Per2 promoter Modulation of circadian rhythm by Magel2 could involve regulation of Clock:Bmal1-mediated transcription, which can be measured by ectopic expression of reporter constructs in tissue culture cells [38]
Summary
Prader-Willi syndrome (PWS) is a genetic neurodevelopmental disorder featuring neonatal failure to thrive, hyperphagia leading to obesity, growth hormone deficiency, and other findings [1,2,3]. Using running wheel activity monitoring, we previously found that gene-targeted Magel2-deficient mice had reduced and more fragmented total activity, with a diminished circadian amplitude [7]. They had more activity during the subjective day compared to wild-type mice, but had a normal circadian period. We discovered progressive infertility in these mice, with irregular estrus cycles in female mice that mimic those seen in other circadian mutant mice [8,9] These and other findings of endocrine disruption [10] support a role for loss of MAGEL2 in the hypothalamic disruption observed in PWS. Magel is a member of the MAGE family of proteins that have various roles in cellular function, but the specific function of Magel is unknown
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