Sensory defects in Necdin deficient mice result from a loss of sensory neurons correlated within an increase of developmental programmed cell death.
Sensory defects in Necdin deficient mice result from a loss of sensory neurons correlated within an increase of developmental programmed cell death.
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DOI：
10.1186/1471-213x-6-56
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发表时间：
2006-11-20
影响因子：
--
通讯作者：
Muscatelli, Francoise
中科院分区：
文献类型：
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作者：
Andrieu, David;Meziane, Hamid;Marly, Fabienne;Angelats, Corinne;Fernandez, Pierre-Alain;Muscatelli, Francoise
人类NECDIN基因与神经发育障碍Prader-Willi综合征（PWS）有关。以前，我们报道了一个小鼠Necdin敲除模型与PWS患者类似的缺陷。尽管Necdin的推定作用主要来自体外研究，但其体内功能仍不清楚。在这项研究中，我们调查Necdin缺陷小鼠的感觉运动行为。我们揭示细胞缺陷并分析其原因。我们报告Necdin缺陷小鼠与野生型动物相比的感觉差异。这些差异使我们研究了Necdin缺陷小鼠胚胎中感觉神经元的发育。首先，我们描述了Necdin在发展中的DRG的表达模式，并报告减少了三分之一的背根神经节中指定的感觉神经元，并表明这种神经元的损失是由E13.5，当DRG的感觉神经元指定。同时，我们观察到在E12.5自然发生的细胞死亡波期间神经元凋亡增加了41%。由于假设Necdin是P75 NTR相互作用物，我们观察了Necdin敲除胚胎中表达P75 NTR的细胞群。出乎意料的是，Necdin功能丧失对表达p75 NTR的神经元没有影响，表明在这种情况下Necdin和P75 NTR之间没有直接的遗传相互作用。虽然我们排除了Necdin在脊髓感觉神经元轴突生长的早期发育阶段的作用，这样的作用可能会发生在神经元分化后期。最后，我们还排除了Necdin在发育中的感觉神经元中的抗增殖作用。总的来说，我们的数据清楚地表明，在神经系统的早期发育中，Necdin是一种抗凋亡或存活因子。
The human NECDIN gene is involved in a neurodevelopmental disorder, Prader-Willi syndrome (PWS). Previously we reported a mouse Necdin knock-out model with similar defects to PWS patients. Despite the putative roles attributed to Necdin, mainly from in vitro studies, its in vivo function remains unclear. In this study, we investigate sensory-motor behaviour in Necdin deficient mice. We reveal cellular defects and analyse their cause. We report sensory differences in Necdin deficient mice compared to wild type animals. These differences led us to investigate sensory neuron development in Necdin deficient mouse embryos. First, we describe the expression pattern of Necdin in developing DRGs and report a reduction of one-third in specified sensory neurons in dorsal roots ganglia and show that this neuronal loss is achieved by E13.5, when DRGs sensory neurons are specified. In parallel, we observed an increase of 41% in neuronal apoptosis during the wave of naturally occurring cell death at E12.5. Since it is assumed that Necdin is a P75NTR interactor, we looked at the P75NTR-expressing cell population in Necdin knock-out embryos. Unexpectedly, Necdin loss of function has no effect on p75NTR expressing neurons suggesting no direct genetic interaction between Necdin and P75NTR in this context. Although we exclude a role of Necdin in axonal outgrowth from spinal sensory neurons in early developmental stages; such a role could occur later in neuronal differentiation. Finally we also exclude an anti-proliferative role of Necdin in developing sensory neurons. Overall, our data show clearly that, in early development of the nervous system, Necdin is an anti-apoptotic or survival factor.