1Multimodal Brain Image Analysis Laboratory (MBIAL), National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, 560029 India.
2Department of Psychiatry, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, 560029 India.
NPJ Syst Biol Appl. 2019 May 7;5:17. doi: 10.1038/s41540-019-0094-3. eCollection 2019.
Neuronal migration constitutes an important step in corticogenesis; dysregulation of the molecular mechanisms mediating this crucial step in neurodevelopment may result in various neuropsychiatric disorders. By curating experimental data from published literature, we identified eight functional modules involving Disrupted-in-schizophrenia 1 (DISC1) and its interacting proteins that regulate neuronal migration. We then identified miRNAs and transcription factors (TFs) that form functional feedback loops and regulate gene expression of the DISC1 interactome. Using this curated data, we conducted in-silico modeling of the DISC1 interactome involved in neuronal migration and identified the proteins that either facilitate or inhibit neuronal migrational processes. We also studied the effect of perturbation of miRNAs and TFs in feedback loops on the DISC1 interactome. From these analyses, we discovered that STAT3, TCF3, and TAL1 (through feedback loop with miRNAs) play a critical role in the transcriptional control of DISC1 interactome thereby regulating neuronal migration. To the best of our knowledge, regulation of the DISC1 interactome mediating neuronal migration by these TFs has not been previously reported. These potentially important TFs can serve as targets for undertaking validation studies, which in turn can reveal the molecular processes that cause neuronal migration defects underlying neurodevelopmental disorders. This underscores the importance of the use of in-silico techniques in aiding the discovery of mechanistic evidence governing important molecular and cellular processes. The present work is one such step towards the discovery of regulatory factors of the DISC1 interactome that mediates neuronal migration.
神经元迁移是皮质发生的重要步骤；神经发育过程中调节这一关键步骤的分子机制失调可能导致各种神经精神疾病。通过整理发表文献中的实验数据，我们确定了 8 个功能模块，涉及精神分裂症相关蛋白 1（DISC1）及其相互作用蛋白，这些蛋白调节神经元迁移。然后，我们确定了 miRNA 和转录因子（TFs），它们形成功能反馈回路，调节 DISC1 相互作用组的基因表达。利用这些整理好的数据，我们对参与神经元迁移的 DISC1 相互作用组进行了计算机模拟，并确定了促进或抑制神经元迁移过程的蛋白质。我们还研究了反馈回路中 miRNA 和 TFs 扰动对 DISC1 相互作用组的影响。通过这些分析，我们发现 STAT3、TCF3 和 TAL1（通过与 miRNA 的反馈回路）在 DISC1 相互作用组的转录控制中发挥关键作用，从而调节神经元迁移。据我们所知，这些 TF 对调节神经元迁移的 DISC1 相互作用组的调控以前尚未报道过。这些潜在的重要 TF 可以作为进行验证研究的靶点，这反过来又可以揭示导致神经发育障碍中神经元迁移缺陷的分子过程。这凸显了在辅助发现调控重要分子和细胞过程的机制证据方面使用计算机技术的重要性。本工作是发现调节神经元迁移的 DISC1 相互作用组的调控因子的重要一步。
