中国神经再生研究(英文版) ›› 2026, Vol. 21 ›› Issue (3): 1151-1161.doi: 10.4103/NRR.NRR-D-24-00623

• 原著:脑损伤修复保护与再生 • 上一篇    下一篇

中枢类淋巴系统在认知障碍疾病中的生理和病理功能

  

  • 出版日期:2026-03-15 发布日期:2025-07-05

Cell type–dependent role of transforming growth factor-β signaling on postnatal neural stem cell proliferation and migration

Kierra Ware1 , Joshua Peter1 , Lucas McClain1 , Yu Luo1, 2, 3, *   

  1. 1 Department of Molecular and Cellular Biosciences, University of Cincinnati, Cincinnati, OH, USA;  2 Neuroscience Graduate Program, University of Cincinnati, Cincinnati, OH, USA;  3 Division of Immunobiology, Cincinnati Children’s Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH, USA
  • Online:2026-03-15 Published:2025-07-05
  • Contact: Yu Luo, PhD, luoy2@ucmail.uc.edu.
  • Supported by:
    This study was supported by NIH grants, Nos. R01NS125074, R01AG083164, R01NS107365, and R21NS127177 (to YL), 1F31NS129204-01A1 (to KW) and Albert Ryan Fellowship (to KW).

摘要:

成年啮齿动物的神经发生不断产生对认知可塑性至关重要的新神经元。 虽然人们知道转化生长因子β信号在胚胎神经发生中很重要,但其在出生后神经发生中的作用仍不清楚。为了明确转化生长因子β信号在体外和体内神经发生级联的不同阶段对出生后神经发生的确切作用,实验开发了两种新型诱导和细胞类型特异性小鼠模型,以特异性地沉默mGFAPcre-ALK5fl/fl-Ai9中神经干细胞或DCXcreERT2-ALK5fl/fl-Ai9中未成熟神经母细胞的TGF-β信号。结果显示,外源性 TGF-β 处理会抑制原发性神经干细胞的增殖,同时刺激它们的迁移,而在敲除活化素样激酶 5(ALK5)的原代培养的神经干细胞中,这种效应会消失。 与此相一致的是,在野生型(WT)神经干细胞中用 SB-431542 抑制转化生长因子β信号传导会在抑制神经干细胞迁移的同时刺激其增殖。有趣的是,体内神经干细胞中 转化生长因子β受体的缺失抑制了 mGFAPcre-ALK5fl/fl-Ai9 小鼠出生后神经元的迁移,而 DCXcreERT2-ALK5fl/fl-Ai9 小鼠未成熟神经母细胞中转化生长因子β信号的缺失并不影响这些细胞在海马中的迁移。总之,实验数据支持转化生长因子β信号在神经干细胞增殖和迁移中的双重作用,并为转化生长因子β信号对体内NSC增殖和迁移的细胞类型依赖性要求提供了新见解。

https://orcid.org/0000-0002-7939-5505 (Yu Luo)

关键词: 成体神经发生, 双皮质素, 海马, 迁移, 神经干细胞, 增殖, 转化生长因子β

Abstract: Adult neurogenesis continuously produces new neurons critical for cognitive plasticity in adult rodents.  While it is known transforming growth factor-β signaling is important in embryonic neurogenesis, its role in postnatal neurogenesis remains unclear. In this study, to define the precise role of transforming growth factor-β signaling in postnatal neurogenesis at distinct stages of the neurogenic cascade both in vitro and in vivo, we developed two novel inducible and cell type-specific mouse models to specifically silence transforming growth factor-β signaling in neural stem cells in (mGFAPcre-ALK5fl/fl-Ai9) or immature neuroblasts in (DCXcreERT2-ALK5fl/fl-Ai9). Our data showed that exogenous transforming growth factor-β treatment led to inhibition of the proliferation of primary neural stem cells while stimulating their migration. These effects were abolished in activin-like kinase 5 (ALK5) knockout primary neural stem cells. Consistent with this, inhibition of transforming growth factor-β signaling with SB-431542 in wild-type neural stem cells stimulated proliferation while inhibited the migration of neural stem cells. Interestingly, deletion of transforming growth factor-β receptor in neural stem cells in vivo inhibited the migration of postnatal born neurons in mGFAPcre-ALK5fl/fl-Ai9 mice, while abolishment of transforming growth factor-β signaling in immature neuroblasts in DCXcreERT2-ALK5fl/fl-Ai9 mice did not affect the migration of these cells in the hippocampus. In summary, our data supports a dual role of transforming growth factor-β signaling in the proliferation and migration of neural stem cells in vitro. Moreover, our data provides novel insights on cell type–specific-dependent requirements of transforming growth factor-β signaling on neural stem cell proliferation and migration in vivo.

Key words: adult neurogenesis, doublecortin, hippocampus, migration, neural stem cells, proliferation, transforming growth factor-β