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Abstract：
Nerve growth factor (NGF) exerts multifaceted functions through different stages of life. A missense mutation (R100W) in the beta-NGF gene was found in hereditary sensory autonomic neuropathy V (HSAN V) patients with severe loss of pain perception but without overt cognitive impairment. To better understand the pathogenesis of HSAN V, we generated the first NGFR100W knock in mouse model for HSAN V. We found that the homozygotes exhibited a postnatal lethal phenotype. A majority of homozygous pups died within the first week. Some homozygous pups could ingest more milk and survived up to 2 months by reducing litter size. Whole mount in situ hybridization using E10.5 embryos revealed that, compared to wild type, R100W mutation did not alter the gene expression patterns of TrkA and P75NTR in the homozygotes. We also found that the homozygotes displayed normal embryonic development of major organs (heart, lung, liver, kidney, and spleen). Furthermore, the homozygotes exhibited severe loss of PGP9.5-positive intra-epidermal sensory fibers. Taken together, our results suggest that, as with HSAN V patients, the R100W mutation primarily affects the peripheral sensory nervous system in the mouse model. This novel mouse model makes it possible to further study in vivo how NGFR100W uncouple trophic function from nociception of NGF.
摘要：
神经生长因子（NGF）在生命的不同阶段发挥着多方面的功能。在遗传性感觉自主神经病变V（HSANV）患者中发现了β-NGF基因中的错义突变（R100W），这些患者的疼痛感觉严重丧失，但没有明显的认知障碍。为了更好地了解HSANV的发病机制，我们在HSAN小鼠模型中产生了第一个NGFR100W敲除。我们发现纯合子表现出出生后致死表型。大多数纯合幼崽在第一周内死亡。一些纯合幼崽可以摄取更多的牛奶，并通过减少产仔数存活长达2个月。使用E10.5胚胎进行整体原位杂交显示，与野生型相比，R100W突变不会改变纯合子中TrkA和P75NTR的基因表达模式。我们还发现纯合子显示出正常的主要器官（心脏，肺，肝脏,肾,和脾脏）。此外，纯合子表现出PGP9.5阳性表皮内感觉纤维的严重损失。一起来看,我们的结果表明，与HSANV患者一样，R100W突变主要影响小鼠模型中的外周感觉神经系统。这种新型小鼠模型使得有可能在体内进一步研究NGFR100W如何从NGF的伤害感受中分离营养功能。
