Essential role for the Prader-Willi syndrome protein necdin in axonal outgrowth.
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.
Lee
Syann
S
Department of Medical Genetics, University of Alberta, Edmonton, Alberta, Canada.
Walker
Christine L
CL
Karten
Barbara
B
Kuny
Sharee L
SL
Tennese
Alysa A
AA
O'Neill
Megan A
MA
Wevrick
Rachel
R
D000818:Animals; D000951:Antigens, Neoplasm; D001369:Axons / Q000378:metabolism*; D018385:Centrosome / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D011218:Prader-Willi Syndrome / Q000235:genetics* / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D020798:Two-Hybrid System Techniques; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D064267:Intrinsically Disordered Proteins
D000951:Antigens, Neoplasm; D004268:DNA-Binding Proteins; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D011506:Proteins; D014446:Tyrosine 3-Monooxygenase; C429655:BBS4 protein, human; C510822:MAGEL2 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D064267:Intrinsically Disordered Proteins; C403091:Magel2 protein, mouse; C412364:Zfp312 protein, mouse; C069766:necdin