Necdin and MAGEL2: Candidate Genes for Prader-Willi Syndrome

Rachel Wevrick, Jason R. Bush, Megan A. O’Neill, Alysa A. Tennese, Sharee L. Kuny, Christine L. Walker

Department of Medical Genetics, University of Alberta, Edmonton, Canada

The necdin and MAGEL2 genes are both inactivated in PWS, along with two other protein-coding genes (SNURF/SNRPN and MKRN3) and a gene for a set of regulatory RNAs (IC RNA and snoRNAs).  Necdin and MAGEL2 are highly related proteins that share a conserved 189 amino acid MAGE homology domain.  To determine the etiology of PWS, it is critically important to understand the role of necdin and MAGEL2 deficiency in humans, and to correlate findings in necdin-null and Magel2-null mice with the clinical and pathological findings in PWS.  The necdin (Neurally differentiated Embryonic Carcinoma-cell derived factor) protein is up-regulated during terminal differentiation of neurons; necdin is also expressed in muscle and other tissues.  Expression of Magel2 is developmentally regulated and becomes limited to distinct regions of the hypothalamus by the time of birth. In the adult mouse, Magel2 is expressed only in the suprachiasmatic nucleus, which is responsible for mammalian circadian rhythm.  Our studies suggest that in response to specific developmentally regulated transcription factors, necdin is expressed and interacts with nuclear transcriptional repressor proteins that regulate the exit of neuronal precursor cells from the cell cycle.  We also found that necdin and Magel2 act at the centrosome (microtubule organizing center) to assist conversion of this specialized cytoskeletal structure from one that forms a mitotic spindle in dividing neuronal precursors, to a highly organized structure that is essential for the development and elongation of bundled axonal tracts and for axonal transport in post-mitotic neurons.  We propose that necdin and MAGEL2 are involved in the critical events whereby the transcriptional events that lead to cell cycle exit are coupled to the cytoskeletal events required for terminal differentiation.  Consistent with this hypothesis, we previously determined that loss of function of necdin causes neurological developmental abnormalities of terminal differentiation and axonal outgrowth in mice, mirroring some of the neurodevelopmental abnormalities in PWS.

Our experiments address the biochemical, cellular, and developmental roles of necdin and MAGEL2, as they relate to loss of gene function in PWS.  We have identified a set of proteins that interact with necdin and MAGEL2 and modify their cellular function.  We have examined the developmental patterns of expression of necdin and MAGEL2 in mice, and have used gene knockout mice to examine the effects of loss of gene function on the normal development and physiology of the nervous and other systems.  We have examined the regulation of the necdin and MAGEL2 genes in the cellular subtypes in which they are normally expressed.  In summary, our studies examine the contribution of loss of necdin and MAGEL2 function to the complex neurobehavioral outcomes in individuals with PWS.

Research in the Wevrick laboratory is supported by the Canadian Institutes of Health Research, the Natural Sciences and Engineering Research Council of Canada, and the Alberta Heritage Foundation for Medical Research.