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Human Molecular Genetics Advance Access published online on January 13, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi059
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Human Molecular Genetics © Oxford University Press 2005; all rights reserved

Article

Essential role for the Prader-Willi syndrome protein necdin in axonal outgrowth

Syann Lee 1, Christine L. Walker 2, Barbara Karten 3, Sharee L. Kuny 2, Alysa A. Tennese 2, Megan A. O'Neill 2, and Rachel Wevrick 4*

1 Department of Medical Genetics, University of Alberta, Edmonton, Alberta, Canada; Beth Israel Deaconess Medical Center, 345 Research North, 99 Brookline Ave., Boston, MA 02215
2 Department of Medical Genetics, University of Alberta, Edmonton, Alberta, Canada
3 Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
4 Department of Medical Genetics, University of Alberta, Edmonton, Alberta, Canada; Department of Medical Genetics, 8-42 Medical Sciences Building, University of Alberta, Edmonton, Alberta, Canada T6G 2H7

* To whom correspondence should be addressed.
Rachel Wevrick, E-mail: rachel.wevrick{at}ualberta.ca


  Abstract

Necdin and Magel2 are related proteins inactivated in Prader-Willi syndrome (PWS), a sporadic chromosomal deletion disorder. We demonstrate that necdin and Magel2 bind to and prevent proteasomal degradation of Fez1, a fasciculation and elongation protein implicated in axonal outgrowth and kinesin-mediated transport, and also bind to the Bardet-Biedl syndrome (BBS) protein BBS4 in co-transfected cells. The interactions among necdin, Magel2, Fez1 and BBS4 occur at or near centrosomes. Centrosomal or pericentriolar dysfunction has previously been implicated in BBS and may also be important in the features of PWS that overlap with BBS, such as learning disabilities, hypogonadism, and obesity. Morphological abnormalities in axonal outgrowth and fasciculation manifest in several regions of the nervous system in necdin null mouse embryos, including axons of sympathetic, retinal ganglion cell, serotonergic and catecholaminergic neurons. These data demonstrate that necdin mediates intracellular processes essential for neurite outgrowth and that loss of necdin impinges on axonal outgrowth. We further suggest that loss of necdin contributes to the neurological phenotype of PWS, and raise the possibility that co-deletion of necdin and the related protein Magel2 may explain the lack of single gene mutations in PWS.


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