High-throughput functional analysis of autism genes in zebrafish identifies convergence in dopaminergic and neuroimmune pathways.
High-throughput functional analysis of autism genes in zebrafish identifies convergence in dopaminergic and neuroimmune pathways.
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DOI：
10.1016/j.celrep.2023.112243
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发表时间：
2023-03-28
期刊：
影响因子：
8.8
通讯作者：
中科院分区：
文献类型：
--
作者：
从自闭症谱系障碍（ASD）的基因发现到生物学相关机制的鉴定仍然是一个核心挑战。在这里，我们在斑马鱼突变体的行为，结构和电路水平上对10个ASD基因进行了平行的体内功能分析，揭示了基因功能丧失的独特和重叠效应。全脑映射确定前脑和小脑是大脑大小差异的最重要贡献者，而参与感觉运动控制的区域，特别是多巴胺能区域，与基线大脑活动的改变有关。最后，我们显示了在选择突变体ASD基因功能丧失导致的小胶质细胞的全球增加，暗示神经免疫功能障碍是ASD生物学相关的关键途径。通过分析斑马鱼中10个自闭症基因的功能，Weinschutz门德斯等人在行为、大脑结构和电路水平上识别出不同和重叠的表型。他们确定多巴胺能和小胶质细胞异常是两个基因的会聚点，并暗示神经免疫功能障碍与自闭症生物学有关。
Advancing from gene discovery in autism spectrum disorders (ASDs) to the identification of biologically relevant mechanisms remains a central challenge. Here, we perform parallel in vivo functional analysis of 10 ASD genes at the behavioral, structural, and circuit levels in zebrafish mutants, revealing both unique and overlapping effects of gene loss of function. Whole-brain mapping identifies the forebrain and cerebellum as the most significant contributors to brain size differences, while regions involved in sensory-motor control, particularly dopaminergic regions, are associated with altered baseline brain activity. Finally, we show a global increase in microglia resulting from ASD gene loss of function in select mutants, implicating neuroimmune dysfunction as a key pathway relevant to ASD biology. By analyzing the function of 10 autism genes in zebrafish, Weinschutz Mendes et al. identify distinct and overlapping phenotypes at the behavioral, brain structural, and circuit levels. They identify dopaminergic and microglial abnormalities as a point of convergence for two genes, and implicate neuroimmune dysfunction as relevant to autism biology.
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影响因子：
16.2
作者：
Iossifov I;Ronemus M;Levy D;Wang Z;Hakker I;Rosenbaum J;Yamrom B;Lee YH;Narzisi G;Leotta A;Kendall J;Grabowska E;Ma B;Marks S;Rodgers L;Stepansky A;Troge J;Andrews P;Bekritsky M;Pradhan K;Ghiban E;Kramer M;Parla J;Demeter R;Fulton LL;Fulton RS;Magrini VJ;Ye K;Darnell JC;Darnell RB;Mardis ER;Wilson RK;Schatz MC;McCombie WR;Wigler M
通讯作者：
Wigler M
聚类自闭症：在26个小鼠模型中使用神经解剖学差异来深入了解异质性。
影响因子：
11
作者：
Ellegood, J.;Anagnostou, E.;Babineau, B. A.;Crawley, J. N.;Lin, L.;Genestine, M.;DiCicco-Bloom, E.;Lai, J. K. Y.;Foster, J. A.;Penagarikano, O.;Geschwind, D. H.;Pacey, L. K.;Hampson, D. R.;Laliberte, C. L.;Mills, A. A.;Tam, E.;Osborne, L. R.;Kouser, M.;Espinosa-Becerra, F.;Xuan, Z.;Powell, C. M.;Raznahan, A.;Robins, D. M.;Nakai, N.;Nakatani, J.;Takumi, T.;van Eede, M. C.;Kerr, T. M.;Muller, C.;Blakely, R. D.;Veenstra-VanderWeele, J.;Henkelman, R. M.;Lerch, J. P.
通讯作者：
Lerch, J. P.
影响因子：
64.8
作者：
Iossifov, Ivan;O'Roak, Brian J.;Sanders, Stephan J.;Ronemus, Michael;Krumm, Niklas;Levy, Dan;Stessman, Holly A.;Witherspoon, Kali T.;Vives, Laura;Patterson, Karynne E.;Smith, Joshua D.;Paeper, Bryan;Nickerson, Deborah A.;Dea, Jeanselle;Dong, Shan;Gonzalez, Luis E.;Mandell, Jeffrey D.;Mane, Shrikant M.;Murtha, Michael T.;Sullivan, Catherine A.;Walker, Michael F.;Waqar, Zainulabedin;Wei, Liping;Willsey, A. Jeremy;Yamrom, Boris;Lee, Yoon-ha;Grabowska, Ewa;Dalkic, Ertugrul;Wang, Zihua;Marks, Steven;Andrews, Peter;Leotta, Anthony;Kendall, Jude;Hakker, Inessa;Rosenbaum, Julie;Ma, Beicong;Rodgers, Linda;Troge, Jennifer;Narzisi, Giuseppe;Yoon, Seungtai;Schatz, Michael C.;Ye, Kenny;McCombie, W. Richard;Shendure, Jay;Eichler, Evan E.;State, Matthew W.;Wigler, Michael
通讯作者：
Wigler, Michael
DOI：
10.1126/science.aaz6063
发表时间：
2020-11-27
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Jin X;Simmons SK;Guo A;Shetty AS;Ko M;Nguyen L;Jokhi V;Robinson E;Oyler P;Curry N;Deangeli G;Lodato S;Levin JZ;Regev A;Zhang F;Arlotta P
通讯作者：
Arlotta P
影响因子：
5.3
作者：
Burgess, Harold A.;Granato, Michael
通讯作者：
Granato, Michael