Identification of Pappa and Sall3 as Gli3 direct target genes acting downstream of cilia signaling in corticogenesis.

IF 2.9 2区 医学 Q2 NEUROSCIENCES
Shinjini Basu, Lena Mautner, Kae Whiting, Kerstin Hasenpusch-Theil, Malgorzata Borkowska, Thomas Theil
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引用次数: 0

Abstract

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.

Pappa和Sall3在皮质发生中作为Gli3直接靶基因作用于纤毛信号下游的鉴定。
大脑皮层对高级认知功能至关重要,它依靠庞大的神经元网络来完成高度复杂的神经任务。皮层神经元的准确数量取决于原毛介导的细胞信号传导,以协调皮层干细胞的增殖和分化。虽然最近的研究已经阐明了纤毛在皮质发生中的多重作用,但纤毛信号传导的下游具体机制仍未被充分探索。我们之前的研究表明,通过重新引入Gli3抑制因子,纤毛基因Inpp5e突变小鼠中过量的早期皮质神经元得以恢复。通过比较Inpp5e和Gli3突变体的表达谱,我们发现了新的Gli3靶基因。这种方法强调了转录因子基因Sall3和Pappalysin1(一种参与IGF信号传导的金属蛋白酶)在两个突变体中都是上调的基因。进一步的研究表明,Gli3直接结合Sall3和Pappa增强子并抑制其在背端脑的活性。总的来说,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,最终确保在皮质发生过程中产生足够数量的神经元。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Cerebral cortex
Cerebral cortex 医学-神经科学
CiteScore
6.30
自引率
8.10%
发文量
510
审稿时长
2 months
期刊介绍: Cerebral Cortex publishes papers on the development, organization, plasticity, and function of the cerebral cortex, including the hippocampus. Studies with clear relevance to the cerebral cortex, such as the thalamocortical relationship or cortico-subcortical interactions, are also included. The journal is multidisciplinary and covers the large variety of modern neurobiological and neuropsychological techniques, including anatomy, biochemistry, molecular neurobiology, electrophysiology, behavior, artificial intelligence, and theoretical modeling. In addition to research articles, special features such as brief reviews, book reviews, and commentaries are included.
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