Tspyl2 Loss-of-Function Causes Neurodevelopmental Brain and Behavior Abnormalities in Mice

Li, Qi; Chan, Sum‐Yin; Wong, Kwun Kk; Wei, Ran; Leung, Yu On; Ding, Abby Y.; Hui, Tomy C. K.; Cheung, CW; Chua, Siew E.; Sham, Pak C.; Wu, Ed X.; McAlonan, Gráinne

doi:10.1007/s10519-015-9777-8

Cited by 12 publications

(7 citation statements)

References 59 publications

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“…TSPX interacts with calcium/calmodulin-dependent serine protein kinase (CASK) and modulates the Tbr-1 regulation of the N-methyl-D-aspartate (NMDA) receptor subunit and other neural genes 19353637. Loss-of-function mutation of Tspx in mice results in neurodevelopmental and behavioral abnormalities,3839 suggesting that TSPX could be an essential gene for neurodevelopment and synaptic functions. TSPX has been demonstrated to be an essential component of the RE1-silencing transcription factor/neuron-restrictive silencer factor (REST/NRSF) transcriptional repressor complex, which regulates numerous neuronal genes and could also serve as tumor suppressor for various cancers 40.…”

Section: The Normal Functions Of Tspy and Tspx Genesmentioning

confidence: 99%

Battle of the sexes: contrasting roles of testis-specific protein Y-encoded (TSPY) and TSPX in human oncogenesis

Lau

Kido

2019

Asian J Androl

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The Y-located testis-specific protein Y-encoded (TSPY) and its X-homologue TSPX originated from the same ancestral gene, but act as a proto-oncogene and a tumor suppressor gene, respectively. TSPY has specialized in male-specific functions, while TSPX has assumed the functions of the ancestral gene. Both TSPY and TSPX harbor a conserved SET/NAP domain, but are divergent at flanking structures. Specifically, TSPX contains a C-terminal acidic domain, absent in TSPY. They possess contrasting properties, in which TSPY and TSPX, respectively, accelerate and arrest cell proliferation, stimulate and inhibit cyclin B-CDK1 phosphorylation activities, have no effect and promote proteosomal degradation of the viral HBx oncoprotein, and exacerbate and repress androgen receptor (AR) and constitutively active AR variant, such as AR-V7, gene transactivation. The inhibitory domain has been mapped to the carboxyl acidic domain in TSPX, truncation of which results in an abbreviated TSPX exerting positive actions as TSPY. Transposition of the acidic domain to the C-terminus of TSPY results in an inhibitory protein as intact TSPX. Hence, genomic mutations/aberrant splicing events could generate TSPX proteins with truncated acidic domain and oncogenic properties as those for TSPY. Further, TSPY is upregulated by AR and AR-V7 in ligand-dependent and ligand-independent manners, respectively, suggesting the existence of a positive feedback loop between a Y-located proto-oncogene and male sex hormone/receptors, thereby amplifying the respective male oncogenic actions in human cancers and diseases. TSPX counteracts such positive feedback loop. Hence, TSPY and TSPX are homologues on the sex chromosomes that function at the two extremes of the human oncogenic spectrum.

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Section: The Normal Functions Of Tspy and Tspx Genesmentioning

confidence: 99%

Battle of the sexes: contrasting roles of testis-specific protein Y-encoded (TSPY) and TSPX in human oncogenesis

Lau

Kido

2019

Asian J Androl

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“…Collectively, the data strongly suggest that TSPYL2 and EZH2 dynamically regulated the expression of important synaptic genes in hippocampal neurons. Defects in the fine tuning of gene expression can contribute to the phenotype of our Tspyl2 knockout mice reported previously [ 9 , 10 ]. For example, Egr3 is important for hippocampal long-term potentiation and fear conditioning [ 50 ].…”

Section: Discussionmentioning

confidence: 96%

“…Targeted mutation of Nap1l2 results in abnormal proliferation of neural progenitor cells and the phenotype resembles spina bifida [ 5 ]. By contrast, targeted mutation of Tspyl2 results in impaired hippocampal long term potentiation and behavioral phenotypes [ 6 , 9 , 10 ]. Our group has shown that TSPYL2 directly regulates the transcription of genes for NMDA receptor subunits 2A ( Grin2a ) and 2B ( Grin2b ) in mice [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

TSPYL2 Regulates the Expression of EZH2 Target Genes in Neurons

Liu

Lei

et al. 2018

Mol Neurobiol

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Testis-specific protein, Y-encoded-like 2 (TSPYL2) is an X-linked gene in the locus for several neurodevelopmental disorders. We have previously shown that Tspyl2 knockout mice had impaired learning and sensorimotor gating, and TSPYL2 facilitates the expression of Grin2a and Grin2b through interaction with CREB-binding protein. To identify other genes regulated by TSPYL2, here, we showed that Tspyl2 knockout mice had an increased level of H3K27 trimethylation (H3K27me3) in the hippocampus, and TSPYL2 interacted with the H3K27 methyltransferase enhancer of zeste 2 (EZH2). We performed chromatin immunoprecipitation (ChIP)-sequencing in primary hippocampal neurons and divided all Refseq genes by k-mean clustering into four clusters from highest level of H3K27me3 to unmarked. We confirmed that mutant neurons had an increased level of H3K27me3 in cluster 1 genes, which consist of known EZH2 target genes important in development. We detected significantly reduced expression of genes including Gbx2 and Prss16 from cluster 1 and Acvrl1, Bdnf, Egr3, Grin2c, and Igf1 from cluster 2 in the mutant. In support of a dynamic role of EZH2 in repressing marked synaptic genes, the specific EZH2 inhibitor GSK126 significantly upregulated, while the demethylase inhibitor GSKJ4 downregulated the expression of Egr3 and Grin2c. GSK126 also upregulated the expression of Bdnf in mutant primary neurons. Finally, ChIP showed that hemagglutinin-tagged TSPYL2 co-existed with EZH2 in target promoters in neuroblastoma cells. Taken together, our data suggest that TSPYL2 is recruited to promoters of specific EZH2 target genes in neurons, and enhances their expression for proper neuronal maturation and function.

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“…Glutamate pathology is involved in neurodevelopmental conditions, and CDA1 regulates the expression of genes encoding glutamate receptors. CDA1 KO mice may have neurodevelopmental and behavioral abnormalities due to the disruption of glutamate signaling, mainly manifested as sensorimotor gating impairment, mild hyperactivity, and hypersensitivity to the dopamine agonist amphetamine [ 61 ]. Subsequently, the study found that compared with wild type littermates, the expression of H3K27me3 (a key histone modification important for brain development and neuronal function) in the hippocampus of CDA1 KO mice was upregulated.…”

Section: Function Of Cda1mentioning

confidence: 99%

The Role of Cell Division Autoantigen 1 (CDA1) in Renal Fibrosis of Diabetic Nephropathy

Chen

et al. 2021

BioMed Research International

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The common kidney disease diabetic nephropathy (DN) accounts for significant morbidity and mortality in patients with diabetes, and its effective diagnosis in incipient stages is still lacking. Renal fibrosis is the main pathological feature of DN. Cell division autoantigen 1 (CDA1), a phosphorylated protein encoded by TSPYL2 on the X chromosome, plays a fibrogenic role by modulating the transforming growth factor-β (TGF-β) signaling, but the exact mechanism remains unclear. TGF-β signaling has been recognized as the key factor in promoting the development and progression of DN. At present, strict control of blood sugar and blood pressure can significantly lower the development and progression of DN in the early stages, and many studies have shown that blocking TGF-β signaling can delay the progress of DN. However, TGF-β is a multifunctional cytokine. Its direct intervention may result in increased side effects. Therefore, the targeted intervention of CDA1 not only can block the TGF-β signaling pathway but also can reduce these side effects. In this article, we review the main physiological roles of CDA1, with particular attention to its effect and potential mechanism in the renal fibrosis of DN.

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Tspyl2 Loss-of-Function Causes Neurodevelopmental Brain and Behavior Abnormalities in Mice

Cited by 12 publications

References 59 publications

Battle of the sexes: contrasting roles of testis-specific protein Y-encoded (TSPY) and TSPX in human oncogenesis

Battle of the sexes: contrasting roles of testis-specific protein Y-encoded (TSPY) and TSPX in human oncogenesis

TSPYL2 Regulates the Expression of EZH2 Target Genes in Neurons

The Role of Cell Division Autoantigen 1 (CDA1) in Renal Fibrosis of Diabetic Nephropathy

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