Wang Lei, Cao Jiaxin, Chen Haichao, Ma Yuezhang, Zhang Yishu, Su Xiaomei, Jing Yuhong, Wang Yonggang
Department of Neurology, The Second Hospital and Clinical Medical School, Lanzhou University, Lanzhou, China,
Institute of Anatomy and Histology and Embryology, Neuroscience, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China.
Dev Neurosci. 2025;47(1):40-54. doi: 10.1159/000538656. Epub 2024 Apr 18.
Transcription factor EB (TFEB), a key regulator of autophagy and lysosomal biogenesis, has diverse roles in various physiological processes. Enhancing lysosomal function by TFEB activation has recently been implicated in restoring neural stem cell (NSC) function. Overexpression of TFEB can inhibit the cell cycle of newborn cortical NSCs. It has also been found that TFEB regulates the pluripotency transcriptional network in mouse embryonic stem cells independent of autophagy and lysosomal biogenesis. This study aims to explore the effects of TFEB activation on neurogenesis in vivo through transgenic mice.
We developed a glial fibrillary acidic protein (GFAP)-driven TFEB overexpression mouse model (TFEB GoE) by crossing the floxed TFEB overexpression mice and hGFAP-Cre mice. We performed immunohistochemical and fluorescence staining on brain tissue from newborn mice to assess neurogenesis changes, employing markers such as GFAP, Nestin, Ki67, doublecortin (DCX), Tbr1, and NeuN to trace different stages of neural development and cell proliferation.
TFEB GoE mice exhibited premature mortality, dying 10-20 days after birth. Immunohistochemical analysis revealed significant abnormalities, including disrupted hippocampal structure and cortical layering. Compared to control mice, TFEB GoE mice showed a marked increase in radial glial cells (RGCs) in the hippocampus and cortex, with Ki67 staining indicating these cells were predominantly in a quiescent state. This suggests that TFEB overexpression suppresses RGC proliferation. Additionally, abnormal distributions of migrating neurons and mature neurons were observed, highlighted by DCX, Tbr1, and NeuN staining, indicating a disruption in normal neurogenesis.
This study, using transgenic animals in vivo, revealed that GFAP-driven TFEB overexpression leads to abnormal neural layering in the hippocampus and cortex by dysregulating neurogenesis. Our study is the first to discover the detrimental impact of TFEB overexpression on neurogenesis during embryonic development, which has important reference significance for future TFEB overexpression interventions in NSCs for treatment.
Transcription factor EB (TFEB), a key regulator of autophagy and lysosomal biogenesis, has diverse roles in various physiological processes. Enhancing lysosomal function by TFEB activation has recently been implicated in restoring neural stem cell (NSC) function. Overexpression of TFEB can inhibit the cell cycle of newborn cortical NSCs. It has also been found that TFEB regulates the pluripotency transcriptional network in mouse embryonic stem cells independent of autophagy and lysosomal biogenesis. This study aims to explore the effects of TFEB activation on neurogenesis in vivo through transgenic mice.
We developed a glial fibrillary acidic protein (GFAP)-driven TFEB overexpression mouse model (TFEB GoE) by crossing the floxed TFEB overexpression mice and hGFAP-Cre mice. We performed immunohistochemical and fluorescence staining on brain tissue from newborn mice to assess neurogenesis changes, employing markers such as GFAP, Nestin, Ki67, doublecortin (DCX), Tbr1, and NeuN to trace different stages of neural development and cell proliferation.
TFEB GoE mice exhibited premature mortality, dying 10-20 days after birth. Immunohistochemical analysis revealed significant abnormalities, including disrupted hippocampal structure and cortical layering. Compared to control mice, TFEB GoE mice showed a marked increase in radial glial cells (RGCs) in the hippocampus and cortex, with Ki67 staining indicating these cells were predominantly in a quiescent state. This suggests that TFEB overexpression suppresses RGC proliferation. Additionally, abnormal distributions of migrating neurons and mature neurons were observed, highlighted by DCX, Tbr1, and NeuN staining, indicating a disruption in normal neurogenesis.
This study, using transgenic animals in vivo, revealed that GFAP-driven TFEB overexpression leads to abnormal neural layering in the hippocampus and cortex by dysregulating neurogenesis. Our study is the first to discover the detrimental impact of TFEB overexpression on neurogenesis during embryonic development, which has important reference significance for future TFEB overexpression interventions in NSCs for treatment.
转录因子EB（TFEB）是自噬和溶酶体生物发生的关键调节因子，在各种生理过程中具有多种作用。最近有研究表明，通过激活TFEB增强溶酶体功能与恢复神经干细胞（NSC）功能有关。TFEB的过表达可抑制新生皮质神经干细胞的细胞周期。研究还发现，TFEB在小鼠胚胎干细胞中调节多能性转录网络，且不依赖于自噬和溶酶体生物发生。本研究旨在通过转基因小鼠探索TFEB激活对体内神经发生的影响。
我们通过将携带floxed的TFEB过表达小鼠与hGFAP-Cre小鼠杂交，构建了一种由胶质纤维酸性蛋白（GFAP）驱动的TFEB过表达小鼠模型（TFEB GoE）。我们对新生小鼠的脑组织进行免疫组织化学和荧光染色，以评估神经发生的变化，使用GFAP、巢蛋白（Nestin）、Ki67、双皮质素（DCX）、Tbr1和NeuN等标志物来追踪神经发育和细胞增殖的不同阶段。
TFEB GoE小鼠表现出过早死亡，出生后10 - 20天死亡。免疫组织化学分析显示出明显异常，包括海马结构和皮质分层紊乱。与对照小鼠相比，TFEB GoE小鼠海马和皮质中的放射状胶质细胞（RGCs）显著增加，Ki67染色表明这些细胞主要处于静止状态。这表明TFEB过表达抑制了RGC的增殖。此外，观察到迁移神经元和成熟神经元的分布异常，DCX、Tbr1和NeuN染色突出显示了这一点，表明正常神经发生受到破坏。
本研究利用体内转基因动物揭示，GFAP驱动的TFEB过表达通过失调神经发生导致海马和皮质神经分层异常。我们的研究首次发现TFEB过表达对胚胎发育期间神经发生的有害影响，这对未来NSC中TFEB过表达干预治疗具有重要参考意义。
转录因子EB（TFEB）是自噬和溶酶体生物发生的关键调节因子，在各种生理过程中具有多种作用。最近有研究表明，通过激活TFEB增强溶酶体功能与恢复神经干细胞（NSC）功能有关。TFEB的过表达可抑制新生皮质神经干细胞的细胞周期。研究还发现，TFEB在小鼠胚胎干细胞中调节多能性转录网络，且不依赖于自噬和溶酶体生物发生。本研究旨在通过转基因小鼠探索TFEB激活对体内神经发生的影响。
我们通过将携带floxed的TFEB过表达小鼠与hGFAP-Cre小鼠杂交，构建了一种由胶质纤维酸性蛋白（GFAP）驱动的TFEB过表达小鼠模型（TFEB GoE）。我们对新生小鼠的脑组织进行免疫组织化学和荧光染色，以评估神经发生的变化，使用GFAP、巢蛋白（Nestin）、Ki67、双皮质素（DCX）、Tbr1和NeuN等标志物来追踪神经发育和细胞增殖的不同阶段。
TFEB GoE小鼠表现出过早死亡，出生后10 - 20天死亡。免疫组织化学分析显示出明显异常，包括海马结构和皮质分层紊乱。与对照小鼠相比，TFEB GoE小鼠海马和皮质中的放射状胶质细胞（RGCs）显著增加，Ki67染色表明这些细胞主要处于静止状态。这表明TFEB过表达抑制了RGC的增殖。此外，观察到迁移神经元和成熟神经元的分布异常，DCX、Tbr1和NeuN染色突出显示了这一点，表明正常神经发生受到破坏。
本研究利用体内转基因动物揭示，GFAP驱动的TFEB过表达通过失调神经发生导致海马和皮质神经分层异常。我们的研究首次发现TFEB过表达对胚胎发育期间神经发生的有害影响，这对未来NSC中TFEB过表达干预治疗具有重要参考意义。
