Targeted Mutation (R100W) of the Gene Encoding NGF Leads to Deficits in the Peripheral Sensory Nervous System
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 un...
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doaj-adec7960054d455f8f3166af55f92b012020-11-24T23:06:01ZengFrontiers Media S.A.Frontiers in Aging Neuroscience1663-43652018-11-011010.3389/fnagi.2018.00373427195Targeted Mutation (R100W) of the Gene Encoding NGF Leads to Deficits in the Peripheral Sensory Nervous SystemWanlin Yang0Kijung Sung1Fengli Zhou2Wei Xu3Robert A. Rissman4Robert A. Rissman5Jianqing Ding6Chengbiao Wu7Chengbiao Wu8Department of Neurology and Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaDepartment of Neurosciences, University of California, San Diego, San Diego, CA, United StatesDepartment of Respiratory Medicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, ChinaDepartment of Neurology and Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaDepartment of Neurosciences, University of California, San Diego, San Diego, CA, United StatesVeterans Affairs San Diego Health Care System, San Diego, CA, United StatesDepartment of Neurology and Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaDepartment of Neurosciences, University of California, San Diego, San Diego, CA, United StatesVeterans Affairs San Diego Health Care System, San Diego, CA, United StatesNerve 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.https://www.frontiersin.org/article/10.3389/fnagi.2018.00373/fullhereditary sensory autonomic neuropathy Vnerve growth factorTrkAp75 neurotrophic factor receptorIntraepidermal Nerve Fiber |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Wanlin Yang Kijung Sung Fengli Zhou Wei Xu Robert A. Rissman Robert A. Rissman Jianqing Ding Chengbiao Wu Chengbiao Wu |
spellingShingle |
Wanlin Yang Kijung Sung Fengli Zhou Wei Xu Robert A. Rissman Robert A. Rissman Jianqing Ding Chengbiao Wu Chengbiao Wu Targeted Mutation (R100W) of the Gene Encoding NGF Leads to Deficits in the Peripheral Sensory Nervous System Frontiers in Aging Neuroscience hereditary sensory autonomic neuropathy V nerve growth factor TrkA p75 neurotrophic factor receptor Intraepidermal Nerve Fiber |
author_facet |
Wanlin Yang Kijung Sung Fengli Zhou Wei Xu Robert A. Rissman Robert A. Rissman Jianqing Ding Chengbiao Wu Chengbiao Wu |
author_sort |
Wanlin Yang |
title |
Targeted Mutation (R100W) of the Gene Encoding NGF Leads to Deficits in the Peripheral Sensory Nervous System |
title_short |
Targeted Mutation (R100W) of the Gene Encoding NGF Leads to Deficits in the Peripheral Sensory Nervous System |
title_full |
Targeted Mutation (R100W) of the Gene Encoding NGF Leads to Deficits in the Peripheral Sensory Nervous System |
title_fullStr |
Targeted Mutation (R100W) of the Gene Encoding NGF Leads to Deficits in the Peripheral Sensory Nervous System |
title_full_unstemmed |
Targeted Mutation (R100W) of the Gene Encoding NGF Leads to Deficits in the Peripheral Sensory Nervous System |
title_sort |
targeted mutation (r100w) of the gene encoding ngf leads to deficits in the peripheral sensory nervous system |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Aging Neuroscience |
issn |
1663-4365 |
publishDate |
2018-11-01 |
description |
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. |
topic |
hereditary sensory autonomic neuropathy V nerve growth factor TrkA p75 neurotrophic factor receptor Intraepidermal Nerve Fiber |
url |
https://www.frontiersin.org/article/10.3389/fnagi.2018.00373/full |
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