Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, India.
Institute for Stem Cell Science and Regenerative Medicine, Bangalore, India.
PLoS Genet. 2023 Aug 18;19(8):e1010874. doi: 10.1371/journal.pgen.1010874. eCollection 2023 Aug.
In the mammalian cerebral cortex, the hippocampal primordium (Hcp) occupies a discrete position in the dorsal telencephalic neuroepithelium adjacent to the neocortical primordium (Ncp). We examined transcriptomic and chromatin-level features that distinguish the Hcp from the Ncp in the mouse during the early neurogenic period, embryonic day (E)12.5. ATAC-seq revealed that the Hcp was more accessible than the Ncp at this stage. Motif analysis of the differentially accessible loci in these tissues revealed LHX2 as a candidate transcription factor for modulating gene regulatory networks (GRNs). We analyzed LHX2 occupancy profiles and compared these with transcriptomic data from control and Lhx2 mutant Hcp and Ncp at E12.5. Our results revealed that LHX2 directly regulates distinct genes in the Hcp and Ncp within a set of common pathways that control fundamental aspects of development namely pluripotency, axon pathfinding, Wnt, and Hippo signaling. Loss of Lhx2 caused a decrease in accessibility, specifically in hippocampal chromatin, suggesting that this factor may play a unique role in hippocampal development. We identified 14 genes that were preferentially enriched in the Hcp, for which LHX2 regulates both chromatin accessibility and mRNA expression, which have not thus far been examined in hippocampal development. Together, these results provide mechanistic insight into how LHX2 function in the Hcp may contribute to the process by which the hippocampus acquires features distinct from the neocortex.
在哺乳动物大脑皮层中，海马原基（Hcp）占据背侧端脑神经上皮中与新皮质原基（Ncp）相邻的离散位置。我们检查了在早期神经发生期间（胚胎日 E12.5），在小鼠中区分 Hcp 和 Ncp 的转录组和染色质水平特征。ATAC-seq 显示，在这个阶段，Hcp 比 Ncp 更容易接近。对这些组织中差异可及位点的基序分析表明，LHX2 是调节基因调控网络（GRNs）的候选转录因子。我们分析了 LHX2 占据的谱，并将这些谱与 E12.5 时对照和 Lhx2 突变 Hcp 和 Ncp 的转录组数据进行了比较。我们的结果表明，LHX2 直接调节 Hcp 和 Ncp 中的不同基因，这些基因在控制多能性、轴突路径发现、Wnt 和 Hippo 信号等发育基本方面的一组共同途径内。Lhx2 的缺失导致可及性降低，特别是在海马染色质中，这表明该因子可能在海马发育中发挥独特作用。我们确定了 14 个在 Hcp 中优先富集的基因，LHX2 调节这些基因的染色质可及性和 mRNA 表达，这些基因在海马发育中尚未被研究过。总之，这些结果为 LHX2 在 Hcp 中的功能如何有助于海马获得与新皮质不同的特征的过程提供了机制见解。
