RSPO/LGR signaling regulates proliferation of adult hippocampal neural stem cells.

IF 4 2区 医学 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY STEM CELLS Pub Date : 2024-10-21 DOI:10.1093/stmcls/sxae065
Daniela Valenzuela-Bezanilla, Muriel D Mardones, Maximiliano Galassi, Sebastian B Arredondo, Sebastian H Santibanez, Stephanie Gutierrez-Jimenez, Nicolás Merino-Véliz, Fernando J Bustos, Lorena Varela-Nallar
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Abstract

In the dentate gyrus of the adult hippocampus, neurogenesis from neural stem cells (NSCs) is regulated by Wnt signals from the local microenvironment. The Wnt/β-catenin pathway is active in NSCs, where it regulates proliferation and fate commitment, and subsequently its activity is strongly attenuated. The mechanisms controlling Wnt activity are poorly understood. In stem cells from adult peripheral tissues, secreted R-spondin proteins (RSPO1-4) interact with LGR4-6 receptors and control Wnt signaling strength. Here, we found that RSPO1-3 and LGR4-6 are expressed in the adult dentate gyrus and in cultured NSCs isolated from the adult mouse hippocampus. LGR4-5 expression decreased in cultured NSCs upon differentiation, concomitantly with the reported decrease in Wnt activity. Treatment with RSPO1-3 increased NSC proliferation and the expression of Cyclin D1, but did not induce the expression of Axin2 or RNF43, two well-described Wnt target genes. However, RSPOs enhanced the effect of Wnt3a on Axin2 and RNF43 expression, as well as on Wnt/β-catenin reporter activity, indicating that they can potentiate Wnt activity in NSCs. Moreover, RSPO1-3 were found to be expressed by cultured dentate gyrus astrocytes, a crucial component of the neurogenic niche. In co-culture experiments, the astrocyte-induced proliferation of NSCs was prevented by RSPO2 knockdown in astrocytes and LGR5 knockdown in hippocampal NSCs. Additionally, RSPO2 knockdown in the adult mouse dentate gyrus reduced proliferation of neural stem and progenitor cells in vivo. Altogether, our results indicate that RSPO/LGR signaling is present in the dentate gyrus and plays a crucial role in regulating neural precursor cell proliferation.

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RSPO/LGR 信号调节成体海马神经干细胞的增殖。
在成年海马的齿状回中,神经干细胞(NSC)的神经发生受来自局部微环境的 Wnt 信号调控。Wnt/β-catenin通路在NSCs中非常活跃,它在NSCs中调节增殖和命运承诺,随后其活性被强烈削弱。人们对控制Wnt活性的机制知之甚少。在成体外周组织干细胞中,分泌的R-软骨蛋白(RSPO1-4)与LGR4-6受体相互作用,控制Wnt信号强度。在这里,我们发现,RSPO1-3和LGR4-6在成鼠齿状回和从成鼠海马分离的培养NSCs中均有表达。在培养的 NSCs 中,LGR4-5 在分化过程中表达量减少,与报道的 Wnt 活性降低同步。用RSPO1-3处理可增加NSC的增殖和细胞周期蛋白D1的表达,但不能诱导Axin2或RNF43这两个已被充分描述的Wnt靶基因的表达。然而,RSPOs增强了Wnt3a对Axin2和RNF43表达的影响,以及对Wnt/β-catenin报告活性的影响,这表明它们可以增强NSCs中的Wnt活性。此外,培养的齿状回星形胶质细胞也表达了 RSPO1-3,这是神经源龛的重要组成部分。在共培养实验中,敲除星形胶质细胞中的 RSPO2 和敲除海马 NSCs 中的 LGR5 可阻止星形胶质细胞诱导的 NSCs 增殖。此外,在成年小鼠齿状回中敲除 RSPO2 会减少体内神经干细胞和祖细胞的增殖。总之,我们的研究结果表明,RSPO/LGR 信号传导存在于齿状回中,并在调节神经前体细胞增殖中发挥着至关重要的作用。
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来源期刊
STEM CELLS
STEM CELLS 医学-生物工程与应用微生物
CiteScore
10.30
自引率
1.90%
发文量
104
审稿时长
3 months
期刊介绍: STEM CELLS, a peer reviewed journal published monthly, provides a forum for prompt publication of original investigative papers and concise reviews. STEM CELLS is read and written by clinical and basic scientists whose expertise encompasses the rapidly expanding fields of stem and progenitor cell biology. STEM CELLS covers: Cancer Stem Cells, Embryonic Stem Cells/Induced Pluripotent Stem (iPS) Cells, Regenerative Medicine, Stem Cell Technology: Epigenetics, Genomics, Proteomics, and Metabonomics, Tissue-Specific Stem Cells, Translational and Clinical Research.
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