NeuroD1 induces microglial apoptosis and cannot induce microglia-to-neuron cross-lineage reprogramming

Rao, Yu; Du, Siling; Yang, Bin; Wang, Yuqing; Li, Yuxin; Li, Ruofan; Zhou, Tian; Du, Xiangjuan; He, Yang; Wang, Yafei; Zhou, Xin; Yuan, Ti‐Fei; Mao, Ying; Peng, Bo

doi:10.1016/j.neuron.2021.11.008

Cited by 65 publications

(61 citation statements)

References 72 publications

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“…Therefore, the in vitro NeuroD1 expression level in our experiments was comparable to that of Matsuda et al, and probably our expression level was even higher (Fig. 1 A–C, 120-fold of Matsuda et al [ 3 ] vs. 200-fold of Rao et al [ 1 ]). Obviously, the “low induction efficiency” cannot explain the failure of observing NeuroD1-induced microglia-to-neuron conversion in vitro.…”

Section: Main Textsupporting

confidence: 87%

“…We detected an approximately 200,000-fold upregulation of tdTomato tag expression (Fig. 1 A, E) [ 1 ], comparable to the FLAG tag data of Matsuda et al [ 3 ].…”

Section: Main Textsupporting

confidence: 86%

“…Recently, two latest papers from us and Chun-Li Zhang at UTSW demonstrated that the NeuroD1 cannot induce the glia-to-neuron conversion by microglia [ 1 ] or astrocyte [ 2 ]. The previous “NeuroD1-induced glia-to-neuron conversion” is most likely attributed to the viral leakages and experimental artifacts.…”

Section: Main Textmentioning

confidence: 99%

“…Matsuda and Nakashima said: “We therefore first compared ND1 mRNA expression levels between the experiments of Rao et al and our experiments in vitro. In their study using CAG-ND1-T2A-tdTomato lentivirus , the relative ND1 mRNA expression in ND1-transducedcells was 200-foldhigher than that of control at 2 days after virus infection (Figure S1E in Rao et al [ 1 ] ). However, this level of upregulation may be insufficient to induce MtN conversion.…”

Section: Main Textmentioning

confidence: 99%

“…The “3000-fold upregulation” by Matsuda et al was obtained by a re-analysis from RNA-seq results [ 4 ], which was not shown in their original paper [ 3 ]. In contrast, the ~ 200-fold upregulation result in our study was acquired from qPCR [ 1 ]. The NeuroD1 expression levels cannot be compared under different methods and scenarios.…”

Section: Main Textmentioning

confidence: 99%

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Failure of observing NeuroD1-induced microglia-to-neuron conversion in vitro is not attributed to the low NeuroD1 expression level

Rao

Peng

2022

Mol Brain

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NeuroD1-induced microglia-to-neuron conversion is hotly debated. Recently, we published a paper in Neuron demonstrating that NeuroD1 cannot induce microglia-to-neuron cross-lineage conversion. In the same issue of Neuron, Matsuda et al., who observed the “NeuroD1-induced microglia-to-neuron conversion” phenotype, responded to our study. They claimed that we failed to observe NeuroD1-induced microglia-to-neuron conversion in vitro due to the low NeuroD1 expression efficiency in our experiment. They argued that the NeuroD1 upregulation in our study was around 200-fold (vs. control), whereas the upregulation in Nakashima lab was 3000-fold, 15 times higher than ours. In fact, this is not true. We compared the expression level from the original paper and found that our NeuroD1 expression level was comparable to that of Matsuda et al. (Neuron 101:472–485.e477, 2019), or even higher. Therefore, the failure of observing NeuroD1-induced microglia-to-neuron conversion cannot be attributable to the low expression level.

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Section: Main Textsupporting

confidence: 87%

“…We detected an approximately 200,000-fold upregulation of tdTomato tag expression (Fig. 1 A, E) [ 1 ], comparable to the FLAG tag data of Matsuda et al [ 3 ].…”

Section: Main Textsupporting

confidence: 86%

Section: Main Textmentioning

confidence: 99%

Section: Main Textmentioning

confidence: 99%

Section: Main Textmentioning

confidence: 99%

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Failure of observing NeuroD1-induced microglia-to-neuron conversion in vitro is not attributed to the low NeuroD1 expression level

Rao

Peng

2022

Mol Brain

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Hippocampal neurogenesis and pro‐neurogenic therapies for Alzheimer's disease

Zheng

2022

Anim Models and Exp Med

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Adult hippocampal neurogenesis (AHN) in the hippocampal dentate gyrus (DG) subset enables the neuronal network to encode new information flexibly and update stored content in due time. 1 Though the number of adult-born neurons declines with age, there is increasing evidence of an indispensable role for limited AHN in hippocampusdependent learning, memory and emotional regulation. 2Alzheimer's disease (AD) is the most common cause of dementia in people over age 65. It is characterized by progressive neurodegeneration in the brain, with no treatment to date for halting disease progression. A sea of money has been invested in the development of anti-AD drugs. Two major drug targets include the extracellular amyloid-beta (Aβ) protein and intraneuronal hyperphosphorylated tau. Besides considering the anti-neurodegenerative potential of AHN and other pro-neurogenic treatments, neuroscientists are also trying to develop new drugs to directly facilitate neurogenesis in the AD brain. 3 However, introducing neurogenesis is challenging in AD. The pool of active hippocampal neural stem cells (NSCs) is prone to being progressively depleted due to sustained homeostatic abnormality within the neurogenic niche under AD and accelerated aging. 4 Innate AHN is dysregulated under AD and the underlying mechanisms remain largely unknown, 5 which hinders the development of pro-AHN drugs. Simultaneously, emerging techniques such as cell transplantation and glia-neuron reprogramming also shed new light on the proneurogenic treatment of AD. 3 These strategies may help overcome

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The origin and repopulation of microglia

Zhang

Cao

Zhang

et al. 2021

Developmental Neurobiology

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Microglia are important immune cells in the central nervous system. There is growing interest in the study of microglia due to their implication in neurodevelopment, acute injury, and neuropsychiatric disorders. They undergo birth, death, and regeneration during the lifetime. Although data on the ontogeny of microglia have been studied for decades, the birth and repopulation of microglia remain legendary and mysterious. In this review, we discuss recent studies that provide new insights into the origin and regeneration of microglia. Modulating the development of microglia may offer new therapeutic opportunities for preventing deleterious effects of inflammation and controlling excessive inflammation in brain diseases.

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NeuroD1 induces microglial apoptosis and cannot induce microglia-to-neuron cross-lineage reprogramming

Cited by 65 publications

References 72 publications

Failure of observing NeuroD1-induced microglia-to-neuron conversion in vitro is not attributed to the low NeuroD1 expression level

Failure of observing NeuroD1-induced microglia-to-neuron conversion in vitro is not attributed to the low NeuroD1 expression level

Hippocampal neurogenesis and pro‐neurogenic therapies for Alzheimer's disease

The origin and repopulation of microglia

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