Nurr1 regulates Top IIβ and functions in axon genesis of mesencephalic dopaminergic neurons

Heng, Xin; Jin, Gang; Zhang, Xin; Yang, Dehuang; Zhu, Meizhen; Fu, Shijun; Li, Xuping; Le, Weidong

doi:10.1186/1750-1326-7-4

Cited by 37 publications

(26 citation statements)

References 47 publications

(66 reference statements)

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“…Other genes involved in axon guidance with TOP2B peaks are AGAP3, GNA1, NCK2, CALN and ABLIM1 . Enrichment for the KEGG axon guidance pathway is consistent with TOP2B's previously reported role in axon guidance ( Yang et al, 2000 ; Nur-E-Kamal et al, 2007 ; Lyu and Wang, 2003 ; Nevin et al, 2011 ; Heng et al, 2012 ).…”

Section: Resultssupporting

confidence: 87%

Genome-wide ChIP-seq analysis of human TOP2B occupancy in MCF7 breast cancer epithelial cells

et al. 2015

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We report the whole genome ChIP seq for human TOP2B from MCF7 cells. Using three different peak calling methods, regions of binding were identified in the presence or absence of the nuclear hormone estradiol, as TOP2B has been reported to play a role in ligand-induced transcription. TOP2B peaks were found across the whole genome, 50% of the peaks fell either within a gene or within 5 kb of a transcription start site. TOP2B peaks coincident with gene promoters were less frequently associated with epigenetic features marking active promoters in estradiol treated than in untreated cells. Significantly enriched transcription factor motifs within the DNA sequences underlying the peaks were identified. These included SP1, KLF4, TFAP2A, MYF, REST, CTCF, ESR1 and ESR2. Gene ontology analysis of genes associated with TOP2B peaks found neuronal development terms including axonogenesis and axon guidance were significantly enriched. In the absence of functional TOP2B there are errors in axon guidance in the zebrafish eye. Specific heparin sulphate structures are involved in retinal axon targeting. The glycosaminoglycan biosynthesis–heparin sulphate/heparin pathway is significantly enriched in the TOP2B gene ontology analysis, suggesting changes in this pathway in the absence of TOP2B may cause the axon guidance faults.

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Section: Resultssupporting

confidence: 87%

Genome-wide ChIP-seq analysis of human TOP2B occupancy in MCF7 breast cancer epithelial cells

et al. 2015

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“…These results were in agreement with previous in vivo findings that top IIβ is expressed abundantly in the specific regions of the rat and mouse brain where postmitotic neurons were located (Watanabe et al, ; Tsutsui et al, ; Lyu and Wang, ). They are consistent with previous reports that top IIβ was associated with neurogenesis (Yang et al, ; Nevin et al, ; Heng et al, ). The top IIβ expression pattern in our study was similar to a recent report in which the expression of top IIβ was upregulated in mouse embryonic stem cells undergoing neuronal differentiation (Tiwari et al, ).…”

Section: Discussionsupporting

confidence: 93%

“…However, little is known about the upstream regulation of top IIβ gene expression during neural differentiation. Recently, top IIβ was reported to be a downstream target of Nurr1, and Nurr1 might influence the axon genesis in dopaminergic neurons by regulating top IIβ expression (Heng et al, ). In the present study, we performed experiments to determine whether the transcription factor Sp1 could regulate top IIβ expression in neuronal differentiation.…”

Section: Discussionmentioning

confidence: 99%

Specificity protein 1 regulates topoisomerase IIβ expression in SH‐SY5Y cells during neuronal differentiation

Guo

Cao

Chi

et al. 2014

J of Neuroscience Research

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Topoisomerase IIβ (top IIβ) is a nuclear enzyme with an essential role in neural development. The regulation of top IIβ gene expression during neural differentiation is poorly understood. Functional analysis of top IIβ gene structure displayed a GC box sequence in its transcription promoter, which binds the nuclear transcription factor specificity protein 1 (Sp1). Sp1 regulates gene expression via multiple mechanisms and is essential for early embryonic development. This study seeks to determine whether Sp1 regulates top IIβ gene expression during neuronal differentiation. For this purpose, human neuroblastoma SH-SY5Y cells were induced to neuronal differentiation in the presence of all-trans retinoic acid (RA) for 5 days. After incubation with 10 μM RA for 3-5 days, a majority of the cells exited the cell cycle to become postmitotic neurons, characterized by the presence of longer neurite outgrowths and expression of the neuronal marker microtubule-associated protein-2 (MAP2). Elevated Sp1 and top IIβ mRNA and protein levels were detected and found to be positively correlated with the differentiation stage. Chromatin immunoprecipitation assay demonstrated an increased recruitment of Sp1 to the top IIβ promoter after RA treatment. Mithramycin A, a compound that interferes with Sp1 binding to GC-rich DNA sequences, downregulated the expression of top IIβ, resulting in reduced expression of MAP2 and decreased neurite length compared with the control group. Our results indicate that Sp1 regulates top IIβ expression by binding to the GC box of the gene promoter during neuronal differentiation in SH-SY5Y cells.

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“…Moreover, a de novo mutation in Top1 and de novo mutations in genes that interact with Top1 and Top3b were identified recently in patients with autism (8,9), whereas deletion of Top3b increases the risk for schizophrenia and intellectual disability (10,11). Top2b is also required for axon outgrowth in different regions of the nervous system and for the survival of postmitotic neurons (12)(13)(14)(15).…”

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confidence: 99%

Topoisomerase 1 inhibition reversibly impairs synaptic function

Mabb

Kullmann

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Topotecan is a topoisomerase 1 (TOP1) inhibitor that is used to treat various forms of cancer. We recently found that topotecan reduces the expression of multiple long genes, including many neuronal genes linked to synapses and autism. However, whether topotecan alters synaptic protein levels and synapse function is currently unknown. Here we report that in primary cortical neurons, topotecan depleted synaptic proteins that are encoded by extremely long genes, including Neurexin-1, Neuroligin-1, Cntnap2, and GABA A β3. Topotecan also suppressed spontaneous network activity without affecting resting membrane potential, action potential threshold, or neuron health. Topotecan strongly suppressed inhibitory neurotransmission via pre-and postsynaptic mechanisms and reduced excitatory neurotransmission. The effects on synaptic protein levels and inhibitory neurotransmission were fully reversible upon drug washout. Collectively, our findings suggest that TOP1 controls the levels of multiple synaptic proteins and is required for normal excitatory and inhibitory synaptic transmission.synapse | topoisomerase | transcription T opoisomerase inhibitors such as topotecan (Hycamtin) are widely used to treat multiple forms of cancer, including brain metastases, ovarian cancer, and small cell lung cancer (1). Topoisomerases resolve DNA supercoiling during cell division and during gene transcription (2). Type I topoisomerases, encoded by Top1, Top3a, and Top3b in mammals, resolve supercoiling by cleaving a single strand of DNA, whereas type II topoisomerases, encoded by Top2a and Top2b, cleave both DNA strands (2). Recently, both types of topoisomerases were associated with neurodevelopment (3-5). For instance, topoisomerase 1 (TOP1) and topoisomerase 2 (TOP2) inhibitors transcriptionally up-regulate the paternal copy of Ubiquitin-protein ligase E3A (Ube3a) (5), a gene that affects synaptic activity and that is deleted or duplicated in distinct neurodevelopmental disorders (Angelman syndrome and autism, respectively) (6, 7). Moreover, a de novo mutation in Top1 and de novo mutations in genes that interact with Top1 and Top3b were identified recently in patients with autism (8, 9), whereas deletion of Top3b increases the risk for schizophrenia and intellectual disability (10, 11). Top2b is also required for axon outgrowth in different regions of the nervous system and for the survival of postmitotic neurons (12-15).TOP1 is localized primarily in the nucleus of postmitotic neurons and is expressed throughout the developing and adult brain (16), suggesting a nuclear function. Indeed, we recently found that topotecan, a selective TOP1 inhibitor, reduced the expression of extremely long genes (>200 kb) in postmitotic neurons by impairing transcription elongation (17). Topotecan and related camptothecin analogs inhibit TOP1 by covalently trapping the enzyme on DNA (2). TOP1 inhibitors also reduce the expression of long genes in cancer cell lines (17-19), revealing a gene length-dependent component to transcription that is common to sev...

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Nurr1 regulates Top IIβ and functions in axon genesis of mesencephalic dopaminergic neurons

Cited by 37 publications

References 47 publications

Genome-wide ChIP-seq analysis of human TOP2B occupancy in MCF7 breast cancer epithelial cells

Genome-wide ChIP-seq analysis of human TOP2B occupancy in MCF7 breast cancer epithelial cells

Specificity protein 1 regulates topoisomerase IIβ expression in SH‐SY5Y cells during neuronal differentiation

Topoisomerase 1 inhibition reversibly impairs synaptic function

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