Smitha A S, Akash Kumar Singh, Jaya Lakshmi P R, Rohini Bhatt, Prajjval Mishra, M Eswaramoorthy, Sourav Banerjee, Tapas K Kundu
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Previous work from our laboratory has shown that a small molecule activator, TTK21, specific to CBP/p300, when conjugated to glucose-derived carbon nanospheres (CSP), is efficiently delivered to the mouse brain and could induce dendritic branching and extend long-term memory. However, the molecular mechanisms of p300 acetyltransferase activity-dependent enhanced dendritogenesis are yet to be understood. Here, we report that CSP-TTK21 treatment to primary neuronal culture derived from mouse embryo enhances the expression of five critical genes: <i>Neurod1</i> (central nervous system development), <i>Tubb3</i> (immature neural marker), <i>Camk2a</i> (synaptic plasticity and LTP), <i>Snap25</i> (spine morphogenesis plasticity), and <i>Scn2a</i> (propagation of the action potential). 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引用次数: 0
摘要
表观遗传修饰在神经发生过程中起着关键作用。在这些修饰中,可逆乙酰化对胚胎和成年神经发生过程中的基因表达进行了微调。CBP/KAT3A 及其同源物 p300/KAT3B 是著名的赖氨酸乙酰转移酶,具有转录共激活能力,参与神经可塑性和记忆。由于缺乏可穿过血脑屏障的 p300/CBP 调制剂,因此无法研究它们的 KAT 活性在神经发生和记忆中的专属作用。我们实验室之前的工作表明,一种特异于 CBP/p300 的小分子激活剂 TTK21 与葡萄糖衍生的碳纳米球(CSP)共轭后,能有效地输送到小鼠大脑,并能诱导树突分支和延长长期记忆。然而,p300乙酰转移酶活性依赖性增强树突发生的分子机制尚不清楚。在此,我们报告了 CSP-TTK21 处理小鼠胚胎原始神经元培养物可增强五个关键基因的表达:Neurod1(中枢神经系统发育)、Tubb3(未成熟神经标记)、Camk2a(突触可塑性和 LTP)、Snap25(脊柱形态发生可塑性)和 Scn2a(动作电位的传播)。通过诱导 p300/CBP KAT 活性激活这些基因,可能会促进成体神经元祖细胞的成熟和分化,从而在齿状回的粒下区形成长而高分支的双皮质素阳性功能神经元。
p300/CBP KATs Are Critical for Maturation and Differentiation of Adult Neural Progenitors.
Epigenetic modifications play a pivotal role in the process of neurogenesis. Among these modifications, reversible acetylation fine-tunes gene expression for both embryonic and adult neurogenesis. The CBP/KAT3A and its paralogue p300/KAT3B are well-known lysine acetyltransferases with transcriptional coactivation ability that engage in neural plasticity and memory. The exclusive role of their KAT activity in neurogenesis and memory could not be addressed due to the absence of a p300/CBP modulator, which can cross the blood-brain barrier. Previous work from our laboratory has shown that a small molecule activator, TTK21, specific to CBP/p300, when conjugated to glucose-derived carbon nanospheres (CSP), is efficiently delivered to the mouse brain and could induce dendritic branching and extend long-term memory. However, the molecular mechanisms of p300 acetyltransferase activity-dependent enhanced dendritogenesis are yet to be understood. Here, we report that CSP-TTK21 treatment to primary neuronal culture derived from mouse embryo enhances the expression of five critical genes: Neurod1 (central nervous system development), Tubb3 (immature neural marker), Camk2a (synaptic plasticity and LTP), Snap25 (spine morphogenesis plasticity), and Scn2a (propagation of the action potential). Activation of these genes by inducing the p300/CBP KAT activity presumably promotes the maturation and differentiation of adult neuronal progenitors and thereby the formation of long and highly branched doublecortin-positive functional neurons in the subgranular zone of the dentate gyrus.
期刊介绍:
ACS Chemical Biology provides an international forum for the rapid communication of research that broadly embraces the interface between chemistry and biology.
The journal also serves as a forum to facilitate the communication between biologists and chemists that will translate into new research opportunities and discoveries. Results will be published in which molecular reasoning has been used to probe questions through in vitro investigations, cell biological methods, or organismic studies.
We welcome mechanistic studies on proteins, nucleic acids, sugars, lipids, and nonbiological polymers. The journal serves a large scientific community, exploring cellular function from both chemical and biological perspectives. It is understood that submitted work is based upon original results and has not been published previously.