Basu Shinjini, Mautner Lena, Whiting Kae, Hasenpusch-Theil Kerstin, Borkowska Malgorzata, Theil Thomas
Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom.
Simons Initiative for the Developing Brain, University of Edinburgh Hugh Robson Building, Edinburgh, United Kingdom.
Cereb Cortex. 2024 Dec 3;34(12). doi: 10.1093/cercor/bhae480.
The cerebral cortex is critical for advanced cognitive functions and relies on a vast network of neurons to carry out its highly intricate neural tasks. Generating cortical neurons in accurate numbers hinges on cell signaling orchestrated by primary cilia to coordinate the proliferation and differentiation of cortical stem cells. While recent research has shed light on multiple ciliary roles in corticogenesis, specific mechanisms downstream of cilia signaling remain largely unexplored. We previously showed that an excess of early-born cortical neurons in mice mutant for the ciliary gene Inpp5e was rescued by re-introducing Gli3 repressor. By comparing expression profiles between Inpp5e and Gli3 mutants, we here identified novel Gli3 target genes. This approach highlighted the transcription factor gene Sall3 and Pappalysin1 (Pappa), a metalloproteinase involved in IGF signaling, as upregulated genes in both mutants. Further examination revealed that Gli3 directly binds to Sall3 and Pappa enhancers and suppresses their activity in the dorsal telencephalon. Collectively, our analyses provide important mechanistic insights into how primary cilia govern the behavior of neural stem cells, ultimately ensuring the production of adequate numbers of neurons during corticogenesis.
大脑皮层对于高级认知功能至关重要，并且依赖于庞大的神经元网络来执行其高度复杂的神经任务。精确数量的皮层神经元的生成取决于由初级纤毛精心编排的细胞信号传导，以协调皮层干细胞的增殖和分化。虽然最近的研究揭示了纤毛在皮层发生中的多种作用，但纤毛信号传导下游的具体机制在很大程度上仍未被探索。我们之前表明，通过重新引入Gli3阻遏物，可以挽救纤毛基因Inpp5e突变小鼠中过多的早期出生的皮层神经元。通过比较Inpp5e和Gli3突变体之间的表达谱，我们在此鉴定了新的Gli3靶基因。这种方法突出了转录因子基因Sall3和Pappalysin1（Pappa，一种参与胰岛素样生长因子信号传导的金属蛋白酶）作为两个突变体中的上调基因。进一步的研究表明，Gli3直接与Sall3和Pappa增强子结合，并抑制它们在背侧端脑的活性。总体而言，我们的分析为初级纤毛如何控制神经干细胞的行为提供了重要的机制见解，最终确保在皮层发生过程中产生足够数量的神经元。
