Damage-Induced Neuronal Endopeptidase Is Critical for Presynaptic Formation of Neuromuscular Junctions
Damage-Induced Neuronal Endopeptidase Is Critical for Presynaptic Formation of Neuromuscular Junctions
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DOI：
10.1523/jneurosci.4521-09.2010
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发表时间：
2010-05-19
影响因子：
5.3
通讯作者：
Kiyama, Hiroshi
中科院分区：
文献类型：
--
作者：
Nagata, Kenichi;Kiryu-Seo, Sumiko;Kiyama, Hiroshi
损伤性神经元内肽酶（DINE）是一种属于神经元内肽酶家族的金属蛋白酶。在胚胎发育期间以及轴突损伤后，主要在中枢神经系统和周围神经系统的神经元亚群中观察到DINE mRNA的表达。然而，DINE及其底物的生理功能尚不清楚。我们制造了DINE缺陷小鼠来检验DINE的生理作用。出生后不久，这些老鼠死于由膈肌功能障碍引起的呼吸衰竭，膈肌严重萎缩。由于DINE在运动神经元中大量表达，膈肌萎缩，我们分析了DINE缺乏小鼠运动神经与骨骼肌之间的相互作用。尽管在dine缺陷小鼠中脊髓的运动神经元数量或从脊髓到骨骼肌的神经轨迹没有明显的缺陷，但详细的组织化学分析表明，从胚胎第12.5天开始，横膈膜的神经末梢树突明显减少。与最终分支的减少相一致，DINE-deficient小鼠膈肌只出现少数神经肌肉连接。其他骨骼肌，包括背阔肌和肋间肌，神经末梢形态也有类似的变化。这些数据表明，DINE是远端轴突进入肌肉以建立神经肌肉连接的关键分子。
Damage-induced neuronal endopeptidase (DINE) is a metalloprotease belonging to the neprilysin family. Expression of DINE mRNA is observed predominantly in subsets of neurons in the CNS and peripheral nervous system during embryonic development, as well as after axonal injury. However, the physiological function of DINE and its substrate remain unknown. We generated DINE-deficient mice to examine the physiological role of DINE. Shortly after birth, these mice died of respiratory failure resulting from a dysfunction of the diaphragm, which showed severe atrophy. As DINE was abundantly expressed in motor neurons and there was atrophy of the diaphragm, we analyzed the interaction between motor nerves and skeletal muscles in the DINE-deficient mice. Although there were no obvious deficiencies in numbers of motor neurons in the spinal cord or in the nerve trajectories from the spinal cord to the skeletal muscle in DINE-deficient mice, detailed histochemical analysis demonstrated a significant decrease of nerve terminal arborization in the diaphragm from embryonic day 12.5. In accordance with the decrease of final branching, the diaphragms from DINE-deficient mice exhibited only a few neuromuscular junctions. Similar changes in nerve terminal morphology were also apparent in other skeletal muscles, including the latissimus dorsi and the intercostal muscles. These data suggest that DINE is a crucial molecule in distal axonal arborization into muscle to establish neuromuscular junctions.