Yunnan Key Laboratory of Cell Metabolism and Diseases, Center for Life Sciences, School of Life Sciences, Yunnan University, Kunming, 650500, China.
BMC Genomics. 2024 Aug 2;25(1):757. doi: 10.1186/s12864-024-10672-w.
It is known that the neurodevelopmental disorder associated gene, Satb2, plays important roles in determining the upper layer neuron specification. However, it is not well known how this gene regulates other neocortical regions during the development. It is also lack of comprehensive delineation of its spatially regulatory pathways in neocortical development.
In this work, we utilized spatial transcriptomics and immuno-staining to systematically investigate the region-specific gene regulation of Satb2 by comparing the Satb2 and Satb2 mice at embryonic stages, including the ventricle zone (VZ) or subventricle zone (SVZ), intermediate zone (IZ) and cortical plate (CP) respectively. The staining result reveals that these three regions become moderately or significantly thinner in the Satb2 mice. In the cellular level, the cell number increases in the VZ/SVZ, whereas the cell number decreases in the CP. The spatial transcriptomics data show that many important genes and relevant pathways are dysregulated in Satb2 mice in a region-specific manner. In the VZ/SVZ, the key genes involved in neural precursor cell proliferation, including the intermediate progenitor marker Tbr2 and the lactate production related gene Ldha, are up-regulated in Satb2 mice. In the IZ, the key genes in regulating neuronal differentiation and migration, such as Rnd2, exhibit ectopic expressions in the Satb2 mice. In the CP, the lineage-specific genes, Tbr1 and Bcl11b, are abnormally expressed. The neuropeptide related gene Npy is down-regulated in Satb2 mice. Finally, we validated the abnormal expressions of key regulators by using immunofluorescence or qPCR.
In summary, our work provides insights on the region-specific genes and pathways which are regulated by Satb2 in neocortical development.
已知与神经发育障碍相关的基因 Satb2 在决定上层神经元特化方面发挥着重要作用。然而，人们并不清楚该基因在发育过程中如何调节其他新皮层区域。此外，其在新皮层发育中的空间调控途径也缺乏全面的描述。
在这项工作中，我们利用空间转录组学和免疫染色技术，通过比较 Satb2 和 Satb2 小鼠在胚胎阶段的 VZ 或 SVZ、IZ 和 CP 等区域，系统地研究了 Satb2 对特定区域基因的调控。染色结果表明，Satb2 小鼠的这三个区域都变得中等或明显变薄。在细胞水平上，VZ/SVZ 中的细胞数量增加，而 CP 中的细胞数量减少。空间转录组学数据显示，Satb2 小鼠中许多重要基因和相关通路以区域特异性方式失调。在 VZ/SVZ 中，参与神经前体细胞增殖的关键基因，包括中间祖细胞标记物 Tbr2 和与乳酸产生相关的基因 Ldha，在 Satb2 小鼠中上调。在 IZ 中，调节神经元分化和迁移的关键基因，如 Rnd2，在 Satb2 小鼠中呈现异位表达。在 CP 中，谱系特异性基因 Tbr1 和 Bcl11b 异常表达。Satb2 小鼠中与神经肽相关的基因 Npy 下调。最后，我们通过免疫荧光或 qPCR 验证了关键调节剂的异常表达。
总之，我们的工作提供了 Satb2 在新皮层发育中调控特定区域基因和途径的见解。
