Essential role for the Prader-Willi syndrome protein necdin in axonal outgrowth
Essential role for the Prader-Willi syndrome protein necdin in axonal outgrowth
复制标题
DOI：
10.1093/hmg/ddi059
复制
发表时间：
2005-03-01
影响因子：
3.5
通讯作者：
Wevrick, R
中科院分区：
文献类型：
--
作者：
Lee, S;Walker, CL;Wevrick, R
Necdin和Magel 2是在Prader-Willi综合征（PWS）（一种散发性染色体缺失疾病）中失活的相关蛋白。我们证明，necdin和Magel 2结合，并防止蛋白酶体降解的Fez 1，一个fasciculation和伸长蛋白牵连轴突生长和驱动蛋白介导的运输，并结合Bardet-Biedl综合征（BBS）蛋白BBS 4在共转染细胞。necdin、Magel 2、Fez 1和BBS 4之间的相互作用发生在中心体或中心体附近。中心体或中心粒周围功能障碍以前曾与BBS有关，也可能在与BBS重叠的PWS特征中很重要，如学习障碍、性腺功能减退和肥胖。necdin基因敲除小鼠胚胎神经系统的几个区域出现轴突生长和成束的形态学异常，包括交感神经、视网膜神经节细胞、肾上腺素能和儿茶酚胺能神经元的轴突。这些数据表明，necdin介导的神经突起生长所必需的细胞内过程和损失的necdin冲击轴突生长。我们进一步表明，necdin的损失有助于PWS的神经系统表型，并提出necdin和相关蛋白Magel 2的共缺失可能解释PWS中缺乏单基因突变的可能性。
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.