Southey Bruce R, Rodriguez-Zas Sandra L
Department of Animal Sciences, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
Department of Statistics, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
Biomedicines. 2022 Apr 10;10(4):877. doi: 10.3390/biomedicines10040877.
Migraine is often accompanied by exacerbated sensitivity to stimuli and pain associated with alternative splicing of genes in signaling pathways. Complementary analyses of alternative splicing of neuropeptide prohormone and receptor genes involved in cell-cell communication in the trigeminal ganglia and nucleus accumbens regions of mice presenting nitroglycerin-elicited hypersensitivity and control mice were conducted. De novo sequence assembly detected 540 isoforms from 168 neuropeptide prohormone and receptor genes. A zero-inflated negative binomial model that accommodates for potential excess of zero isoform counts enabled the detection of 27, 202, and 12 differentially expressed isoforms associated with hypersensitivity, regions, and the interaction between hypersensitivity and regions, respectively. Skipped exons and alternative 3' splice sites were the most frequent splicing events detected in the genes studied. Significant differential splicing associated with hypersensitivity was identified in CALCA and VGF neuropeptide prohormone genes and ADCYAP1R1, CRHR2, and IGF1R neuropeptide receptor genes. The prevalent region effect on differential isoform levels (202 isoforms) and alternative splicing (82 events) were consistent with the distinct splicing known to differentiate central nervous structures. Our findings highlight the changes in alternative splicing in neuropeptide prohormone and receptor genes associated with hypersensitivity to pain and the necessity to target isoform profiles for enhanced understanding and treatment of associated disorders such as migraine.
偏头痛常伴有对刺激的敏感性加剧以及与信号通路中基因可变剪接相关的疼痛。对呈现硝酸甘油诱发的超敏反应的小鼠和对照小鼠的三叉神经节和伏隔核区域中参与细胞间通讯的神经肽前体激素和受体基因的可变剪接进行了补充分析。从头序列组装从168个神经肽前体激素和受体基因中检测到540种异构体。一个用于处理零异构体计数潜在过量情况的零膨胀负二项式模型分别检测到与超敏反应、区域以及超敏反应和区域之间相互作用相关的27种、202种和12种差异表达的异构体。跳过外显子和可变3'剪接位点是在所研究基因中检测到的最常见的剪接事件。在CALCA和VGF神经肽前体激素基因以及ADCYAP1R1、CRHR2和IGF1R神经肽受体基因中鉴定出与超敏反应相关的显著差异剪接。对差异异构体水平（202种异构体）和可变剪接（82个事件）普遍存在的区域效应与已知区分中枢神经结构的独特剪接一致。我们的研究结果突出了神经肽前体激素和受体基因中与疼痛超敏反应相关的可变剪接变化，以及针对异构体谱以增强对偏头痛等相关疾病的理解和治疗的必要性。
