Zhou Yuqiu, Tao Li, Zhu Ying
State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Institutes of Brain Science and Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai 200032, China.
Brain Sci. 2023 Jul 13;13(7):1070. doi: 10.3390/brainsci13071070.
Development is a complex process involving precise regulation. Developmental regulation may vary in tissues and individuals, and is often altered in disorders. Currently, the regulation of developmental timing across neocortical areas and developmental changes in Down syndrome (DS) brains remain unclear. The changes in regulation are often accompanied by changes in the gene expression trajectories, which can be divided into two scenarios: (1) changes of gene expression trajectory shape that reflect changes in cell type composition or altered molecular machinery; (2) temporal shift of gene expression trajectories that indicate different regulation of developmental timing. Therefore, we developed an R package TempShift to separates these two scenarios and demonstrated that TempShift can distinguish temporal shift from different shape (DiffShape) of expression trajectories, and can accurately estimate the time difference between multiple trajectories. We applied TempShift to identify sequential gene expression across 11 neocortical areas, which suggested sequential occurrence of synapse formation and axon guidance, as well as reconstructed interneuron migration pathways within neocortex. Comparison between healthy and DS brains revealed increased microglia, shortened neuronal migration process, and delayed synaptogenesis and myelination in DS. These applications also demonstrate the potential of TempShift in understanding gene expression temporal dynamics during different biological processes.
发育是一个涉及精确调控的复杂过程。发育调控在不同组织和个体中可能存在差异，并且在疾病状态下常常发生改变。目前，新皮质区域发育时间的调控以及唐氏综合征（DS）大脑中的发育变化仍不清楚。调控的变化通常伴随着基因表达轨迹的改变，这可分为两种情况：（1）基因表达轨迹形状的变化，反映细胞类型组成的改变或分子机制的变化；（2）基因表达轨迹的时间偏移，表明发育时间的不同调控。因此，我们开发了一个R包TempShift来区分这两种情况，并证明TempShift可以区分表达轨迹的时间偏移与不同形状（DiffShape），并能准确估计多条轨迹之间的时间差异。我们应用TempShift来识别11个新皮质区域的顺序基因表达，这表明突触形成和轴突导向是顺序发生的，同时还重建了新皮质内中间神经元的迁移途径。健康大脑与DS大脑的比较显示，DS大脑中小胶质细胞增多、神经元迁移过程缩短、突触发生和髓鞘形成延迟。这些应用还证明了TempShift在理解不同生物学过程中基因表达时间动态方面的潜力。
