Zhang Yu, Zhang Tao, Xu Lian, Zhu Ye, Zhao Li-Li, Li Xiao-Di, Yang Wei-Wei, Chen Jing, Gu Miao, Gu Xiao-Song, Yang Jian
School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu Province, China.
Key Laboratory of Neuroregeneration of Jiangsu Province and Ministry of Education, Co-innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, Jiangsu Province, China.
Neural Regen Res. 2022 Nov;17(11):2484-2490. doi: 10.4103/1673-5374.339010.
Egfr, a member of the ErbB gene family, plays a critical role in tissue development and homeostasis, wound healing, and disease. However, expression and regulators of Egfr during spinal cord development remain poorly understood. In this study, we investigated ErbB evolution and analyzed co-expression modules, miRNAs, and transcription factors that may regulate Egfr expression in rats. We found that ErbB family members formed via Egfr duplication in the ancient vertebrates but diverged after speciation of gnathostomes. We identified a module that was co-expressed with Egfr, which involved cell proliferation and blood vessel development. We predicted 25 miRNAs and nine transcription factors that may regulate Egfr expression. Dual-luciferase reporter assays showed six out of nine transcription factors significantly affected Egfr promoter reporter activity. Two of these transcription factors (KLF1 and STAT3) inhibited the Egfr promoter reporter, whereas four transcription factors (including FOXA2) activated the Egfr promoter reporter. Real-time PCR and immunofluorescence experiments showed high expression of FOXA2 during the embryonic period and FOXA2 was expressed in the floor plate of the spinal cord, suggesting the importance of FOXA2 during embryonic spinal cord development. Considering the importance of Egfr in embryonic spinal cord development, wound healing, and disease (specifically in cancer), regulatory elements identified in this study may provide candidate targets for nerve regeneration and disease treatment in the future.
表皮生长因子受体（Egfr）是ErbB基因家族的成员之一，在组织发育与稳态、伤口愈合及疾病过程中发挥关键作用。然而，脊髓发育过程中Egfr的表达及调控因子仍知之甚少。在本研究中，我们探究了ErbB的进化，并分析了可能调控大鼠Egfr表达的共表达模块、微小RNA（miRNA）及转录因子。我们发现，ErbB家族成员在古代脊椎动物中通过Egfr复制形成，但在有颌类动物物种形成后发生了分化。我们鉴定出一个与Egfr共表达的模块，其涉及细胞增殖和血管发育。我们预测了25个可能调控Egfr表达的miRNA和9个转录因子。双荧光素酶报告基因检测显示，9个转录因子中有6个显著影响Egfr启动子报告基因的活性。其中两个转录因子（KLF1和STAT3）抑制Egfr启动子报告基因，而4个转录因子（包括FOXA2）激活Egfr启动子报告基因。实时定量聚合酶链反应（Real-time PCR）和免疫荧光实验显示，FOXA2在胚胎期高表达，且在脊髓底板表达，提示FOXA2在胚胎脊髓发育过程中的重要性。鉴于Egfr在胚胎脊髓发育、伤口愈合及疾病（特别是癌症）中的重要性，本研究中鉴定出的调控元件可能为未来的神经再生和疾病治疗提供候选靶点。
