August 2021
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26 Reads
[This corrects the article DOI: 10.1371/journal.pbio.3000435.].
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August 2021
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26 Reads
[This corrects the article DOI: 10.1371/journal.pbio.3000435.].
December 2020
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205 Reads
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7 Citations
The main stem cell niche for neurogenesis in the adult mammalian brain is the subventricular zone (SVZ) that extends along the cerebral lateral ventricles. We aimed at characterizing the initial molecular responses of the macaque monkey SVZ to transient, global cerebral ischemia. We microdissected tissue lining the anterior horn of the lateral ventricle (SVZa) from 7 day post-ischemic and sham-operated monkeys. Transcriptomics shows that in ischemic SVZa, 541 genes were upregulated and 488 genes were down-regulated. The transcription data encompassing the upregulated genes revealed a profile typical for quiescent stem cells and astrocytes. In the primate brain the SVZ is morphologically subdivided in distinct and separate ependymal and subependymal regions. The subependymal contains predominantly neural stem cells (NSC) and differentiated progenitors. To determine in which SVZa region ischemia had evoked transcriptional upregulation, sections through control and ischemic SVZa were analyzed by high-throughput in situ hybridization for a total of 150 upregulated genes shown in the www.monkey-niche.org image database. The majority of the differentially expressed genes mapped to the subependymal layers on the striatal or callosal aspect of the SVZa. Moreover, a substantial number of upregulated genes was expressed in the ependymal layer, implicating a contribution of the ependyma to stem cell biology. The transcriptome analysis yielded several novel gene markers for primate SVZa including the apelin receptor that is strongly expressed in the primate SVZa niche upon ischemic insult.
March 2020
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206 Reads
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18 Citations
The circadian clock is a cell-autonomous time-keeping mechanism established gradually during embryonic development. Here, we generated a transgenic zebrafish line carrying a destabilized fluorescent protein driven by the promoter of a core clock gene, nr1d1, to report in vivo circadian rhythm at the single-cell level. By time-lapse imaging of this fish line and 3D reconstruction, we observed the sequential initiation of the reporter expression starting at photoreceptors in the pineal gland, then spreading to the cells in other brain regions at the single-cell level. Even within the pineal gland, we found heterogeneous onset of nr1d1 expression, in which each cell undergoes circadian oscillation superimposed over a cell type–specific developmental trajectory. Furthermore, we found that single-cell expression of nr1d1 showed synchronous circadian oscillation under a light–dark (LD) cycle. Remarkably, single-cell oscillations were dramatically dampened rather than desynchronized in animals raised under constant darkness, while the developmental trend still persists. It suggests that light exposure in early zebrafish embryos has significant effect on cellular circadian oscillations.
November 2019
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195 Reads
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16 Citations
Scientific Reports
Aberrant histone acetylation contributes to age-dependent cognitive decline and neurodegenerative diseases. We analyze the function of lysine acetyltransferase TIP60/KAT5 in neurons of the hippocampus using an inducible mouse model. TIP60-deficiency in the adult forebrain leads within days to extensive transcriptional dysfunction characterized by the presence of a neurodegeneration-related signature in CA1. Cell cycle- and immunity-related genes are upregulated while learning- and neuronal plasticity-related genes are downregulated. The dysregulated genes seen under TIP60-deficiency overlap with those in the well-characterized CK-p25 neurodegeneration model. We found that H4K12 is hypoacetylated at the transcriptional start sites of those genes whose expression is dampened in TIP60-deficient mice. Transcriptional dysregulation is followed over a period of weeks by activation of Caspase 3 and fragmentation of β-actin in CA1 neurites, eventually leading to severe neuronal loss. TIP60-deficient mice also develop mild memory impairment. These phenotypes point to a central role of TIP60 in transcriptional networks that are critical for neuronal viability.
July 2019
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62 Reads
Circadian clock is a cell-autonomous time-keeping mechanism established gradually during embryonic development. Here we generated a transgenic zebrafish line carrying a destabilized fluorescent protein driven by the promoter of a core clock gene, nr1d1, to report in vivo circadian rhythm at the single-cell level. By time-lapse imaging of this fish line, we observed the sequential initiation of the reporter expression starting at photoreceptors in pineal gland then spreading to cells in other brain regions. Even within pineal gland, we found heterogeneous onset of nr1d1 expression in which each cell undergoes circadian oscillation superimposed over cell-type specific developmental trajectory. Furthermore, we found that single-cell expression of nr1d1 showed synchronous circadian oscillation under light-dark cycle. Remarkably, single-cell oscillations were lost in animals raised under constant darkness while developmental trend still persists. It suggests that light exposure in early clock development initializes cellular clocks rather than synchronizes existing individual oscillators as previously believed.
May 2019
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5 Reads
December 2018
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269 Reads
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13 Citations
Translational Neurodegeneration
Background Circadian rhythms are oscillating physiological and behavioral changes governed by an internal molecular clock, and dysfunctions in circadian rhythms have been associated with ageing and various neurodegenerative diseases. However, the evidence directly connecting the neurodegeneration-associated proteins to circadian control at the molecular level remains sparse. Methods Using meta-analysis, synchronized animals and cell lines, cells and tissues from FUS R521C knock-in rats, we examined the role of FUS in circadian gene expression regulation. Results We found that FUS, an oscillating expressed nuclear protein implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), exerted a novel feedback route to regulate circadian gene expression. Nr1d1-encoded core circadian protein REV-ERBα bound the Fus promoter and regulated the expression of Fus. Meanwhile, FUS was in the same complex as PER/CRY, and repressed the expression of E box-containing core circadian genes, such as Per2, by mediating the promoter occupancy of PSF-HDAC1. Remarkably, a common pathogenic mutant FUS (R521C) showed increased binding to PSF, and caused decreased expression of Per2. Conclusions Therefore, we have demonstrated FUS as a modulator of circadian gene expression, and provided novel mechanistic insights into the mutual influence between circadian control and neurodegeneration-associated proteins. Electronic supplementary material The online version of this article (10.1186/s40035-018-0131-y) contains supplementary material, which is available to authorized users.
October 2018
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10 Reads
October 2018
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3 Reads
October 2018
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10 Reads
... Thymus (10) (4) (7), (12) bens, in the olfactory system with areas such as the olfactory bulb, olfactory tubercle, nucleus of the lateral olfactory tract and cortical regions related to olfaction (entorhinal and piriform cortex) (3,(5)(6)(7)15,22). A recent article by our team showed that APLNR is expressed in the subventricular region located in the caudate nucleus, an area related to neurogenesis (22). ...
December 2020
... 28,29 In support of this idea, studies in zebrafish showed that cyclic expression of a reporter gene driven by the nr1d1 promoter starts in the pineal photoreceptors and then spreads to other brain regions. 30 In addition, per2 expression has been shown to be higher in the pineal gland than in other regions, 31 as are many accessory clock genes. 32 Pineal-less mutants also show reduced amplitude in behavioural rhythms, 33 a similar effect to that found after blocking its molecular oscillator (Ben-Moshe Livne et al. 19 see below). ...
March 2020
... At present, Tip60 participates in many cellular processes such as transcriptional regulation, cell cycle control, apoptosis, autophagy, and DNA repair [23][24][25][26][27]. Based on previous reports, Tip60 expression is high in the hippocampal CA1 region in adult mice [28]. Tamoxifen-induced conditional Tip60 deficiency in postmitotic excitatory neurons of the adult forebrain reduced H4K12 acetylation and the dysregulation of gene expression in the hippocampal CA1 region [29]. Inflammation and neurodegeneration in the CA1 region gradually progressed through Tip60 deficiency, and Tip60-deficient mice showed modest memory impairment at a later time point [29]. ...
November 2019
Scientific Reports
... Physiological FUS is a transcription factor [523] which has been identified to regulate circadian gene expression via a novel feedback effect [601]. FUS mutations interfere with RNA metabolic pathways and suppress protein translation [602]. ...
December 2018
Translational Neurodegeneration
... With the discovery of new FUS mutations, researchers continue to establish several novel transgenic animal models to gain a more comprehensive understanding of how FUS mutations contribute to ALS. These models not only involve the overexpression of mutant forms but may also incorporate precise gene editing technologies such as CRISPR/Cas9 (Zhang et al., 2018). Researchers are dedicated to delving into the interactions between FUS and other proteins such as TDP-43 in the pathogenesis of ALS (Loughlin and Wilce, 2019). ...
September 2018
Neurobiology of Aging
... PSMD5 gene has also been found to be associated with residual feed intake in pigs (Liu et al., 2016). PHF19 gene has been found to be associated with nervous system development (Liu et al., 2014). TRAF1 gene has been found to be associated with immune response in swine (Galindo and Alonso, 2017). ...
October 2014