Genomic imprinting results in the selective expression of either the maternal or paternal copy of a gene, and transcriptional repression of the other allele by epigenetic mechanisms. A number of imprinted genes are linked to brain development and function, yet the roles of many of these genes, and even of imprinting itself, are unclear. Now, Stewart and colleagues have investigated the role of one imprinted gene, mage-like 2 (MAGEL2), in the brain.
MAGEL2 is one of a cluster of paternally expressed genes, the loss of which underlies Prader-Willi Syndrome (PWS), which is characterized by obesity, sleep disorders, hyperphagia and hypogonadism. The authors set out to understand how loss of MAGEL2 contributes to the PWS phenotype.
They showed that, in the mouse brain, most MAGEL2-containing cells are found in the hypothalamus. High levels of Magel2 expression were observed in neurons in the dorsal suprachiasmatic nucleus (SCN) that convey circadian pacemaking signals to peripheral tissues. Magel2 expression in the SCN fluctuated rhythmically, peaking during dark periods when the mice were most active.
To determine the role of Magel2 in generating circadian output, the authors examined mice in which the paternal copy of the Magel2 gene was absent (Magel2 m+/p- mice) and there was a resultant complete loss of the protein. These mice exhibited altered feeding and breeding behaviour. Furthermore, although the mice demonstrated daily rhythms of running behaviour, overall daytime activity was reduced, indicating that Magel2 is important for the normal control of several circadian behaviours.
Many of the behaviours that were altered in these mice are modulated by orexins, a family of hypothalamic neuropeptides. The authors showed that the levels of orexins in the SCN and the lateral hypothalamus were reduced in the Magel2m+/p- mice, suggesting that the effects of Magel2 on the circadian rhythmicity of activity, feeding and breeding might be mediated by these neuropeptides.
This study shows that MAGEL2 is important for normal hypothalamic function and the regulation of circadian behaviours and reveals a possible connection with orexin-mediated signalling. In turn, this links the absence of MAGEL2 to many of the PWS symptoms. However, the advantages of the paternal-specific expression of this gene remain undetermined.