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

Hum Mol Genet. 2005 Mar 1;14(5):627-37. doi: 10.1093/hmg/ddi059. Epub 2005 Jan 13.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Neoplasm
  • Axons / metabolism*
  • Centrosome / metabolism
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Humans
  • Immunohistochemistry
  • Mice
  • Microtubule-Associated Proteins
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / metabolism
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism
  • Prader-Willi Syndrome / genetics*
  • Prader-Willi Syndrome / metabolism
  • Proteins / genetics
  • Proteins / metabolism
  • Two-Hybrid System Techniques
  • Tyrosine 3-Monooxygenase / metabolism

Substances

  • Antigens, Neoplasm
  • BBS4 protein, human
  • DNA-Binding Proteins
  • MAGEL2 protein, human
  • Magel2 protein, mouse
  • Microtubule-Associated Proteins
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Proteins
  • Zfp312 protein, mouse
  • necdin
  • Tyrosine 3-Monooxygenase