Transcriptomics analysis reveals potential regulatory role of nSMase2 (Smpd3) in nervous system development and function of middle-aged mouse brains

IF 2.4 4区 心理学 Q2 BEHAVIORAL SCIENCES
Zhihui Zhu, Timothy S. McClintock, Erhard Bieberich
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Abstract

Neutral sphingomyelinase-2 (nSMase2), gene name sphingomyelin phosphodiesterase-3 (Smpd3), is a key regulatory enzyme responsible for generating the sphingolipid ceramide. The function of nSMase2 in the brain is still controversial. To better understand the functional roles of nSMase2 in the aging mouse brain, we applied RNA-seq analysis, which identified a total of 1462 differentially abundant mRNAs between +/fro and fro/fro, of which 891 were increased and 571 were decreased in nSMase2-deficient mouse brains. The most strongly enriched GO and KEGG annotation terms among transcripts increased in fro/fro mice included synaptogenesis, synapse development, synaptic signaling, axon development, and axonogenesis. Among decreased transcripts, enriched annotations included ribosome assembly and mitochondrial protein complex functions. KEGG analysis of decreased transcripts also revealed overrepresentation of annotations for Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington disease (HD). Ingenuity Pathway Analysis (IPA) tools predicted lower susceptibility to these neurodegenerative disorders, as well as predictions agreeing with stronger synaptic function, learning, and memory in fro/fro mice. The IPA tools identified signaling proteins, epigenetic regulators, and microRNAs as likely upstream regulators of the broader set of genes encoding the affected transcripts. It also revealed 16 gene networks, each linked to biological processes identified as overrepresented annotations among the affected transcripts by multiple analysis methods. Therefore, the analysis of these RNA-seq data indicates that nSMase2 impacts synaptic function and neural development, and may contribute to the onset and development of neurodegenerative diseases in middle-aged mice.

Abstract Image

转录组学分析揭示了 nSMase2 (Smpd3) 在中年小鼠大脑神经系统发育和功能中的潜在调控作用。
中性鞘磷脂酶-2(nSMase2),基因名称为鞘磷脂磷酸二酯酶-3(Smpd3),是一种负责生成鞘磷脂神经酰胺的关键调节酶。关于 nSMase2 在大脑中的功能,目前仍存在争议。为了更好地了解nSMase2在衰老小鼠大脑中的功能作用,我们应用RNA-seq分析鉴定了+/fro和fro/fro之间共1462个差异丰富的mRNA,其中891个在nSMase2缺陷小鼠大脑中增加,571个减少。在fro/fro小鼠增加的转录本中,GO和KEGG注释词的富集程度最高,包括突触发生、突触发育、突触信号转导、轴突发育和轴突生成。在减少的转录本中,丰富的注释包括核糖体组装和线粒体蛋白复合体功能。对减少的转录本进行的 KEGG 分析还显示,阿尔茨海默病(AD)、帕金森病(PD)和亨廷顿病(HD)的注释比例过高。Ingenuity Pathway Analysis(IPA)工具预测,蛙/蛙小鼠对这些神经退行性疾病的易感性较低,而且预测结果与蛙/蛙小鼠更强的突触功能、学习能力和记忆力一致。IPA 工具发现信号转导蛋白、表观遗传调节因子和 microRNA 可能是编码受影响转录本的更广泛基因集的上游调节因子。它还揭示了 16 个基因网络,每个网络都与通过多种分析方法确定为受影响转录本中高比例注释的生物过程有关。因此,对这些 RNA-seq 数据的分析表明,nSMase2 会影响突触功能和神经发育,并可能导致中年小鼠神经退行性疾病的发生和发展。
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来源期刊
Genes Brain and Behavior
Genes Brain and Behavior 医学-行为科学
CiteScore
6.80
自引率
4.00%
发文量
62
审稿时长
4-8 weeks
期刊介绍: Genes, Brain and Behavior was launched in 2002 with the aim of publishing top quality research in behavioral and neural genetics in their broadest sense. The emphasis is on the analysis of the behavioral and neural phenotypes under consideration, the unifying theme being the genetic approach as a tool to increase our understanding of these phenotypes. Genes Brain and Behavior is pleased to offer the following features: 8 issues per year online submissions with first editorial decisions within 3-4 weeks and fast publication at Wiley-Blackwells High visibility through its coverage by PubMed/Medline, Current Contents and other major abstracting and indexing services Inclusion in the Wiley-Blackwell consortial license, extending readership to thousands of international libraries and institutions A large and varied editorial board comprising of international specialists.
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