Neurodevelopmental origins of structural and psychomotor defects in CXCR4-linked primary immunodeficiency.

IF 14.7 1区 医学 Q1 NEUROSCIENCES
Giulia Demenego, Sara Mancinelli, Antonella Borreca, Rosalba Olga Proce, Vanessa Aragona, Matteo Miotto, Marco Cremonesi, Laura Zucchelli, Irene Corradini, Eugene Kim, Katarina Ilic, Edoardo Fraviga, Luca Pellegrino, Raffaele Badolato, Roberto Rusconi, Davide Pozzi, Marinos Kallikourdis, Diana Cash, Michela Matteoli, Simona Lodato
{"title":"Neurodevelopmental origins of structural and psychomotor defects in CXCR4-linked primary immunodeficiency.","authors":"Giulia Demenego, Sara Mancinelli, Antonella Borreca, Rosalba Olga Proce, Vanessa Aragona, Matteo Miotto, Marco Cremonesi, Laura Zucchelli, Irene Corradini, Eugene Kim, Katarina Ilic, Edoardo Fraviga, Luca Pellegrino, Raffaele Badolato, Roberto Rusconi, Davide Pozzi, Marinos Kallikourdis, Diana Cash, Michela Matteoli, Simona Lodato","doi":"10.1016/j.neuron.2025.05.016","DOIUrl":null,"url":null,"abstract":"<p><p>Inborn errors of immunity (IEI), as congenital chronic disorders, are often associated with neurobehavioral symptoms, traditionally considered secondary to patient burden. Their origin, however, has yet to be addressed. Here, we found that IEI-associated genes are expressed in neural lineages during human brain development, and in the absence of immunological challenges, IEI mutations directly impair neurodevelopmental trajectories, leading to psychomotor defects. Warts hypogammaglobulinemia immunodeficiency myelokathexis (WHIM) mice-bearing a mutation causing Cxcr4 hyperactivation-show developmental foliation defects of the cerebellum correlating with sensorimotor and affective dysfunctions, which recapitulate the alterations described in patients. WHIM cerebella single-cell profiling revealed major transcriptional deregulation in granule cell progenitors, whose aberrant proliferation and migration induce foliation and circuit defects. AMD3100 intracerebroventricular injection rescues both morphological and behavioral defects, demonstrating their brain-specific and Cxcr4-dependent origin. Collectively, our findings highlight the relevance of neurodevelopmental implications underlying psychomotor IEI manifestations, broadening our understanding of these conditions beyond immune dysfunctions.</p>","PeriodicalId":19313,"journal":{"name":"Neuron","volume":" ","pages":""},"PeriodicalIF":14.7000,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Neuron","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.neuron.2025.05.016","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
引用次数: 0

Abstract

Inborn errors of immunity (IEI), as congenital chronic disorders, are often associated with neurobehavioral symptoms, traditionally considered secondary to patient burden. Their origin, however, has yet to be addressed. Here, we found that IEI-associated genes are expressed in neural lineages during human brain development, and in the absence of immunological challenges, IEI mutations directly impair neurodevelopmental trajectories, leading to psychomotor defects. Warts hypogammaglobulinemia immunodeficiency myelokathexis (WHIM) mice-bearing a mutation causing Cxcr4 hyperactivation-show developmental foliation defects of the cerebellum correlating with sensorimotor and affective dysfunctions, which recapitulate the alterations described in patients. WHIM cerebella single-cell profiling revealed major transcriptional deregulation in granule cell progenitors, whose aberrant proliferation and migration induce foliation and circuit defects. AMD3100 intracerebroventricular injection rescues both morphological and behavioral defects, demonstrating their brain-specific and Cxcr4-dependent origin. Collectively, our findings highlight the relevance of neurodevelopmental implications underlying psychomotor IEI manifestations, broadening our understanding of these conditions beyond immune dysfunctions.

cxcr4相关原发性免疫缺陷的结构和精神运动缺陷的神经发育起源。
先天性免疫错误(IEI)作为先天性慢性疾病,通常与神经行为症状相关,传统上认为继发于患者负担。然而,它们的起源尚未得到解决。在这里,我们发现IEI相关基因在人类大脑发育过程中的神经谱系中表达,并且在没有免疫挑战的情况下,IEI突变直接损害神经发育轨迹,导致精神运动缺陷。疣低γ球蛋白血症免疫缺陷性骨髓增生(WHIM)小鼠-携带导致Cxcr4过度激活的突变-显示小脑发育叶面缺陷与感觉运动和情感功能障碍相关,这概括了患者所描述的改变。WHIM小脑单细胞谱揭示了颗粒细胞祖细胞的主要转录失调,其异常增殖和迁移诱导叶状和回路缺陷。AMD3100脑室内注射可挽救形态学和行为缺陷,证明其脑特异性和cxcr4依赖性的起源。总的来说,我们的发现强调了精神运动性IEI表现的神经发育意义的相关性,扩大了我们对这些疾病的理解,超出了免疫功能障碍。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
Neuron
Neuron 医学-神经科学
CiteScore
24.50
自引率
3.10%
发文量
382
审稿时长
1 months
期刊介绍: Established as a highly influential journal in neuroscience, Neuron is widely relied upon in the field. The editors adopt interdisciplinary strategies, integrating biophysical, cellular, developmental, and molecular approaches alongside a systems approach to sensory, motor, and higher-order cognitive functions. Serving as a premier intellectual forum, Neuron holds a prominent position in the entire neuroscience community.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:604180095
Book学术官方微信