Caubit Xavier, Arbeille Elise, Chabbert Dorian, Desprez Florence, Messak Imane, Fatmi Ahmed, Habermann Bianca, Gubellini Paolo, Fasano Laurent
Aix-Marseille University, CNRS, IBDM, UMR 7288, Marseille, France.
Front Genet. 2021 Jul 12;12:683959. doi: 10.3389/fgene.2021.683959. eCollection 2021.
mice have been widely used to study the postnatal function of several genes in forebrain projection neurons, including cortical projection neurons (CPNs) and striatal medium-sized spiny neurons (MSNs). We linked heterozygous deletion of gene to autism spectrum disorder (ASD) and used mice to investigate the postnatal function of , which is expressed by CPNs but not MSNs. Recently, single-cell transcriptomics of the adult mouse striatum revealed the expression of in interneurons and showed expression in striatal cholinergic interneurons (SCINs), which are attracting increasing interest in the field of ASD. These data and the phenotypic similarity between the mice with haploinsufficiency and -dependent conditional deletion of () prompted us to better characterize the expression of and the activity of transgene in the striatum. Here, we show that the great majority of -expressing cells are SCINs and that all SCINs express . Using lineage tracing, we demonstrate that the transgene is expressed in the SCIN lineage where it can efficiently elicit the deletion of the floxed allele. Moreover, transcriptomic and bioinformatic analysis in mice showed dysregulated striatal expression of a number of genes, including genes whose human orthologues are associated with ASD and synaptic signaling. These findings identifying the expression of the transgene in SCINs lineage lead to a reappraisal of the interpretation of experiments using -dependent gene manipulations. They are also useful to decipher the cellular and molecular substrates of the ASD-related behavioral abnormalities observed in mouse models.
小鼠已被广泛用于研究前脑投射神经元中多个基因的产后功能，包括皮质投射神经元（CPNs）和纹状体中型棘状神经元（MSNs）。我们将某基因的杂合缺失与自闭症谱系障碍（ASD）联系起来，并使用某小鼠来研究该基因的产后功能，该基因由CPNs而非MSNs表达。最近，成年小鼠纹状体的单细胞转录组学揭示了某基因在中间神经元中的表达，并显示在纹状体胆碱能中间神经元（SCINs）中有该基因表达，这在ASD领域引起了越来越多的关注。这些数据以及某基因单倍体不足的小鼠与某基因依赖条件性缺失（某）的小鼠之间的表型相似性，促使我们更好地描述某基因在纹状体中的表达以及某转基因的活性。在这里，我们表明绝大多数表达某基因的细胞是SCINs，并且所有SCINs都表达某基因。通过谱系追踪，我们证明某转基因在SCIN谱系中表达，在那里它可以有效地引发floxed等位基因的缺失。此外，对某小鼠的转录组学和生物信息学分析表明，许多基因的纹状体表达失调，包括其人类直系同源基因与ASD和突触信号相关的基因。这些发现确定了某转基因在SCINs谱系中的表达，导致对使用某基因依赖的基因操作的实验解释进行重新评估。它们也有助于解读在某小鼠模型中观察到的与ASD相关的行为异常的细胞和分子基础。
