Selective Expression of Nicotinic Receptor Sub-unit mRNA in Early Human Fetal Forebrain
Selective Expression of Nicotinic Receptor Sub-unit mRNA in Early Human Fetal Forebrain
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DOI：
10.3389/fnmol.2020.00072
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发表时间：
2020-05-21
影响因子：
4.8
通讯作者：
Clowry, Gavin J.
中科院分区：
文献类型：
--
作者：
Alzu'bi, Ayman;Middleham, William;Clowry, Gavin J.
来自动物和人类研究的越来越多的证据表明，在发育过程中暴露于尼古丁，与吸烟的影响分开，可能导致大脑发育失调，包括行为缺陷。一项针对人类胎儿大脑皮质的RNaseq研究表明，人类尼古丁乙酰胆碱（ACh）受体亚基的16个基因中有9个在受孕后7.5至12周（PCW）之间选择性表达。最高表达的亚基基因是CHNRA 4和CHNRB 2，其蛋白产物联合收割机形成在成人脑中表达的最普遍的功能受体同种型。它们在RNAseq样品和通过原位杂交的组织切片中表现出相关表达。与其他皮质标记物的共定位研究表明，它们主要由皮质板和前亚板中的有丝分裂后谷氨酸能神经元前光标表达，而不是皮质祖细胞或GABA能中间神经元前光标。然而，神经节隆起中的GABA能中间神经元祖细胞确实表达这些亚单位。CHNRA5也表现出中等水平的表达，并再次有利于有丝分裂后的神经元。其他子单元，例如，CHRNA7表现出低但可检测的表达水平。发现不表达的CHRN基因包括通常被认为是肌肉特异性的亚基的基因，例如，CHNRA1，尽管检测到一些肌肉特异性基因表达，例如CHNRB1。虽然有很少或根本没有合成乙酰胆碱的内在皮层神经元，胆碱能纤维从基底前脑支配大脑皮层最迟从12 PCW。乙酰胆碱可能对放射状迁移的皮层神经元和GABA能中间神经元祖细胞具有旁分泌作用。
Increasing evidence from animal and human studies indicate that exposure to nicotine during development, separated from the effects of smoking tobacco, can contribute to dysregulation of brain development including behavioral deficits. An RNAseq study of human fetal cerebral cortex demonstrated that 9 out of 16 genes for human nicotinic acetylcholine (ACh) receptor subunits are selectively expressed between 7.5 and 12 post-conceptional weeks (PCW). The most highly expressed subunit genes were CHNRA4 and CHNRB2, whose protein products combine to form the most ubiquitous functional receptor isoform expressed in the adult brain. They exhibited correlated expression in both RNAseq samples, and in tissue sections by in situ hybridization. Co-localization studies with other cortical markers suggest they are pre-dominantly expressed by post-mitotic glutamatergic neuron pre-cursors in both cortical plate and pre-subplate, rather than cortical progenitor cells or GABAergic interneuron pre-cursors. However, GABAergic interneuron progenitor cells in the ganglionic eminences do express these sub-units. CHNRA5 also showed moderate levels of expression and again favored post-mitotic neurons. Other subunits, e.g., CHRNA7, exhibited low but detectable levels of expression. CHRN genes found not to be expressed included genes for subunits usually considered muscle specific, e.g., CHNRA1, although some muscle specific gene expression was detected, for instance CHNRB1. Although there is little or no synthesis of acetylcholine by intrinsic cortical neurons, cholinergic fibers from basal forebrain innervate the cerebral cortex from 12 PCW at the latest. Acetylcholine may have a paracrine effect on radially migrating cortical neurons and GABAergic interneuron progenitors.