Proprioceptive sensory neuropathy in mice with a mutation in the cytoplasmic dynein heavy chain 1 gene
Proprioceptive sensory neuropathy in mice with a mutation in the cytoplasmic dynein heavy chain 1 gene
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DOI：
10.1523/jneurosci.4338-07.2007
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发表时间：
2007-12-26
影响因子：
5.3
通讯作者：
Popko, Brian
中科院分区：
文献类型：
--
作者：
Chen, Xiang-Jun;Levedakou, Eleni N.;Popko, Brian
Mice heterozygous for the radiation-induced Sprawling (Swl) mutation display an early-onset sensory neuropathy with muscle spindle deficiency.尽管这些突变体的后肢运动神经功能正常，但缺乏 H 反射强烈表明本体感觉有缺陷。免疫组织化学分析表明，新生Swll + 小鼠腰椎背根神经节的本体感觉感觉神经元严重受损，而运动神经元数量即使在老年动物中也保持不变。我们使用定位克隆来鉴定该突变体的细胞质动力蛋白重链 1 基因 (Dync1h1) 中的九个碱基对缺失。此外，我们证明 Loa/+ 小鼠（之前已被证明携带 Dync1h1 错义点突变，导致迟发性运动神经元丢失）也出现严重的早发性本体感觉神经病。有趣的是，与 Loa 突变相反，在过度表达人类突变型超氧化物歧化酶 (SOD1(G93A)) 转基因的运动神经元疾病小鼠模型中，Swl 突变不会延迟疾病进展。我们共同提供了体内证据，表明细胞质动力蛋白的不同突变可以导致纯粹的感觉神经病或累及运动神经元的感觉神经病。
Mice heterozygous for the radiation-induced Sprawling (Swl) mutation display an early-onset sensory neuropathy with muscle spindle deficiency. The lack of an H reflex despite normal motor nerve function in the hindlimbs of these mutants strongly suggests defective proprioception. Immunohistochemical analyses reveal that proprioceptive sensory neurons are severely compromised in the lumbar dorsal root ganglia of newborn Swll + mice, whereas motor neuron numbers remain unaltered even in aged animals. We have used positional cloning to identify a nine base-pair deletion in the cytoplasmic dynein heavy chain 1 gene (Dync1h1) in this mutant. Furthermore, we demonstrate that Loa/+ mice, which have previously been shown to carry a missense point mutation in Dync1h1 that results in late-onset motor neuron loss, also present with a severe, early-onset proprioceptive sensory neuropathy. Interestingly, in contrast to the Loa mutation, the Swl mutation does not delay disease progression in a motor neuron disease mouse model overexpressing a human mutant superoxide dismutase (SOD1(G93A)) transgene. Together, we provide in vivo evidence that distinct mutations in cytoplasmic dynein can either result in a pure sensory neuropathy or in a sensory neuropathy with motor neuron involvement.