Disruption of the paternal necdin gene diminishes TrkA signaling for sensory neuron survival
Disruption of the paternal necdin gene diminishes TrkA signaling for sensory neuron survival
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DOI：
10.1523/jneurosci.2083-05.2005
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发表时间：
2005-07-27
影响因子：
5.3
通讯作者：
Yoshikawa, K
中科院分区：
文献类型：
--
作者：
Kuwako, K;Hosokawa, A;Yoshikawa, K
Necdin是一种多功能信号蛋白，稳定有丝分裂后神经元的终末分化。位于染色体15q11-q12的人类Necdin基因是母系印记的，父系转录的，在Prader-Willi综合征中不表达，这是一种与人类基因组印记相关的神经发育障碍。尽管Necdin缺乏的小鼠表现出几种异常的表型，使人想起这种综合征，但人们对导致神经发育缺陷的分子机制知之甚少。在这里，我们证明了父系表达的Necdin对于依赖神经生长因子(NGF)的感觉神经元的生理发育是必需的。父系Necdin等位基因缺陷的小鼠胚胎在背根神经节中缺乏Necdin的表达，而原肌球蛋白相关激酶A(TrkA)受体酪氨酸激酶和p75神经营养素受体正常表达。Necdin与TrkA和p75相互作用，促进这些受体之间的联系。NGF诱导的TrkA和丝裂原活化蛋白激酶在Necdin缺失的感觉神经节中的磷酸化显著减少。此外，缺乏父系Necdin等位基因的小鼠体内感觉神经节细胞凋亡增加，含有P物质的神经元数量减少。这些突变小鼠对热疼痛表现出显著的高耐受性，这种疼痛在Prader-Willi综合征患者中常见。这些结果表明，父系表达的Necdin促进了TrkA信号转导，从而促进了NGF依赖的伤害感受神经元的存活。
Necdin is a multifunctional signaling protein that stabilizes terminal differentiation of postmitotic neurons. The human necdin gene in chromosome 15q11 - q12 is maternally imprinted, paternally transcribed, and not expressed in Prader - Willi syndrome, a human genomic imprinting- associated neurodevelopmental disorder. Although necdin- deficient mice display several abnormal phenotypes reminiscent of this syndrome, little is known about molecular mechanisms that lead to the neurodevelopmental defects. Here, we demonstrate that paternally expressed necdin is required for physiological development of nerve growth factor ( NGF)- dependent sensory neurons. Mouse embryos defective in the paternal necdin allele displayed absent necdin expression in the dorsal root ganglia, in which the tropomyosin- related kinase A ( TrkA) receptor tyrosine kinase and the p75 neurotrophin receptor were expressed in a normal manner. Necdin interacted with both TrkA and p75 to facilitate the association between these receptors. NGF- induced phosphorylation of TrkA and mitogen- activated protein kinase was significantly diminished in the necdin- null sensory ganglia. Furthermore, the mice lacking the paternal necdin allele displayed augmented apoptosis in the sensory ganglia in vivo and had a reduced population of substance P- containing neurons. These mutant mice showed significantly high tolerance to thermal pain, which is often seen in individuals with Prader - Willi syndrome. These results suggest that paternally expressed necdin facilitates TrkA signaling to promote the survival of NGF- dependent nociceptive neurons.