Maturation Delay of Human GABAergic Neurogenesis in Fragile X Syndrome Pluripotent Stem Cells.
Maturation Delay of Human GABAergic Neurogenesis in Fragile X Syndrome Pluripotent Stem Cells.
复制标题
DOI：
10.1093/stcltm/szac022
复制
发表时间：
2022-06-22
影响因子：
6
通讯作者：
Loring, Jeanne F.
中科院分区：
文献类型：
--
作者：
Zhang, Ai;Sokolova, Irina;Domissy, Alain;Davis, Joshua;Rao, Lee;Utami, Kagistia Hana;Wang, Yanling;Hagerman, Randi J.;Pouladi, Mahmoud A.;Sanna, Pietro;Boland, Michael J.;Loring, Jeanne F.
脆性X综合征（FXS）是导致智力残疾和自闭症谱系障碍的主要单基因原因，它是由脆性X智力发育迟滞-1 （FMR1）基因5′-UTR中CGG三核苷酸重复扩增引起的。FMR1的表观遗传沉默导致脆性X智力迟钝蛋白（FMRP）的缺失。尽管迄今为止大多数研究都集中在兴奋性神经元上，但最近的证据表明gaba能抑制网络也受到影响。为了研究人类gaba能神经发生，我们建立了一种从多个FXS中可重复性地获得抑制性神经元并控制人类多能干细胞（hPSC）系的方法。电生理分析表明，发育中的FXS神经元GABA功能开关延迟，这是胎儿发育过程中GABAA通道功能由去极化向超极化转变的过渡，对发育中的大脑产生深远影响。为了研究这种延迟的原因，我们分析了来自gaba能神经发生2个阶段的FXS和对照细胞的14400个单细胞转录组。对照组和FXS细胞在早期时间点相似，但后期FXS细胞保留了成神经细胞增殖相关基因的表达，与对照组相比，动作电位调节、突触和线粒体相关基因的表达水平较低。我们的分析表明，FMRP的缺失延长了祖细胞的增殖阶段，这可能导致更多的神经元在神经发生的后期保持未成熟。这可能对FXS体内稳态兴奋抑制回路的发育具有深远的意义，并为理解疾病机制提供了新的方向，可能有助于指导治疗干预。
Fragile X Syndrome (FXS), the leading monogenic cause of intellectual disability and autism spectrum disorder, is caused by expansion of a CGG trinucleotide repeat in the 5ʹ-UTR of the Fragile X Mental Retardation-1 (FMR1) gene. Epigenetic silencing of FMR1 results in loss of the Fragile X Mental Retardation Protein (FMRP). Although most studies to date have focused on excitatory neurons, recent evidence suggests that GABAergic inhibitory networks are also affected. To investigate human GABAergic neurogenesis, we established a method to reproducibly derive inhibitory neurons from multiple FXS and control human pluripotent stem cell (hPSC) lines. Electrophysiological analyses suggested that the developing FXS neurons had a delay in the GABA functional switch, a transition in fetal development that converts the GABAA channel’s function from depolarization to hyperpolarization, with profound effects on the developing brain. To investigate the cause of this delay, we analyzed 14 400 single-cell transcriptomes from FXS and control cells at 2 stages of GABAergic neurogenesis. While control and FXS cells were similar at the earlier time point, the later-stage FXS cells retained expression of neuroblast proliferation-associated genes and had lower levels of genes associated with action potential regulation, synapses, and mitochondria compared with controls. Our analysis suggests that loss of FMRP prolongs the proliferative stage of progenitors, which may result in more neurons remaining immature during the later stages of neurogenesis. This could have profound implications for homeostatic excitatory-inhibitory circuit development in FXS, and suggests a novel direction for understanding disease mechanisms that may help to guide therapeutic interventions.
登录
查看更多内容
影响因子：
16.2
作者：
Edbauer, Dieter;Neilson, Joel R.;Foster, Kelly A.;Wang, Chi-Fong;Seeburg, Daniel P.;Batterton, Matthew N.;Tada, Tomoko;Dolan, Bridget M.;Sharp, Phillip A.;Sheng, Morgan
通讯作者：
Sheng, Morgan
影响因子：
7
作者：
Castagnola S;Cazareth J;Lebrigand K;Jarjat M;Magnone V;Delhaye S;Brau F;Bardoni B;Maurin T
通讯作者：
Maurin T
DOI：
10.1111/j.1365-2788.2006.00803.x
发表时间：
2006-07-01
影响因子：
3.6
作者：
Lewis, P.;Abbeduto, L.;Schroeder, S.
通讯作者：
Schroeder, S.
影响因子：
25
作者：
Hansen, David V.;Lui, Jan H.;Flandin, Pierre;Yoshikawa, Kazuaki;Rubenstein, John L.;Alvarez-Buylla, Arturo;Kriegstein, Arnold R.
通讯作者：
Kriegstein, Arnold R.
影响因子：
4.3
作者：
Gelfman, Sahar;Wang, Quanli;Eglen, Stephen J.
通讯作者：
Eglen, Stephen J.