scholarly journals A Human-Specific Schizophrenia Risk Tandem Repeat Affects Alternative Splicing of a Human-Unique Isoform AS3MTd2d3 and Mushroom Dendritic Spine Density

2020 ◽  
Author(s):  
Xin Cai ◽  
Zhi-Hui Yang ◽  
Hui-Juan Li ◽  
Xiao Xiao ◽  
Ming Li ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Tandem Repeat ◽  
Dendritic Spines ◽  
Hippocampal Neurons ◽  
Variable Number ◽  
High Linkage Disequilibrium ◽  
Spine Density ◽  
Functional Variation ◽  
Human Specific

Abstract Recent advances in functional genomics have facilitated the identification of multiple genes and isoforms associated with the genetic risk of schizophrenia, yet the causal variations remain largely unclear. A previous study reported that the schizophrenia risk single-nucleotide polymorphism (SNP) rs7085104 at 10q24.32 was in high linkage disequilibrium (LD) with a human-specific variable number of tandem repeat (VNTR), and both were significantly associated with the brain mRNA expression of a human-unique AS3MTd2d3 isoform in Europeans and African Americans. In this study, we have shown the direct regulation of the AS3MTd2d3 mRNA expression by this VNTR through an in vitro minigene splicing assay, suggesting that it is likely a causative functional variation. Intriguingly, we have further confirmed that the VNTR and rs7085104 are significantly associated with AS3MTd2d3 mRNA expression in brains of Han Chinese donors, and rs7085104 is also associated with risk of schizophrenia in East Asians. Finally, the overexpression of AS3MTd2d3 in cultured primary hippocampal neurons results in significantly reduced densities of mushroom dendritic spines, implicating its potential functional impact. Considering the crucial roles of dendritic spines in neuroplasticity, these results reveal the potential regulatory impact of the schizophrenia risk VNTR on AS3MTd2d3 and provide insights into the underlying biological mechanisms.

scholarly journals Human-specific tandem repeat expansion and differential gene expression during primate evolution

2019 ◽  
Vol 116 (46) ◽  
pp. 23243-23253 ◽  
Author(s):  
Arvis Sulovari ◽  
Ruiyang Li ◽  
Peter A. Audano ◽  
David Porubsky ◽  
Mitchell R. Vollger ◽  
...  
Keyword(s):  
Tandem Repeat ◽  
Tandem Repeats ◽  
Sequence Data ◽  
Variable Number ◽  
Specific Expression ◽  
Sequence Composition ◽  
Transcription Profiles ◽  
Long Read ◽  
Repeat Expansions ◽  
Human Specific

Short tandem repeats (STRs) and variable number tandem repeats (VNTRs) are important sources of natural and disease-causing variation, yet they have been problematic to resolve in reference genomes and genotype with short-read technology. We created a framework to model the evolution and instability of STRs and VNTRs in apes. We phased and assembled 3 ape genomes (chimpanzee, gorilla, and orangutan) using long-read and 10x Genomics linked-read sequence data for 21,442 human tandem repeats discovered in 6 haplotype-resolved assemblies of Yoruban, Chinese, and Puerto Rican origin. We define a set of 1,584 STRs/VNTRs expanded specifically in humans, including large tandem repeats affecting coding and noncoding portions of genes (e.g., MUC3A, CACNA1C). We show that short interspersed nuclear element–VNTR–Alu (SVA) retrotransposition is the main mechanism for distributing GC-rich human-specific tandem repeat expansions throughout the genome but with a bias against genes. In contrast, we observe that VNTRs not originating from retrotransposons have a propensity to cluster near genes, especially in the subtelomere. Using tissue-specific expression from human and chimpanzee brains, we identify genes where transcript isoform usage differs significantly, likely caused by cryptic splicing variation within VNTRs. Using single-cell expression from cerebral organoids, we observe a strong effect for genes associated with transcription profiles analogous to intermediate progenitor cells. Finally, we compare the sequence composition of some of the largest human-specific repeat expansions and identify 52 STRs/VNTRs with at least 40 uninterrupted pure tracts as candidates for genetically unstable regions associated with disease.

Alleles of the bovine DGAT1 variable number of tandem repeat associated with a milk fat QTL at chromosome 14 can stimulate gene expression

2006 ◽  
Vol 25 (1) ◽  
pp. 116-120 ◽  
Author(s):  
Rainer Fürbass ◽  
Andreas Winter ◽  
Ruedi Fries ◽  
Christa Kühn
Keyword(s):  
Gene Expression ◽  
Tandem Repeat ◽  
Milk Fat ◽  
Variable Number ◽  
Chromosome 14 ◽  
Fat Percentage ◽  
Vntr Polymorphism ◽  
Causal Mutation

A quantitative trait locus (QTL) affecting milk fat percentage has been mapped to the centromeric end of the bovine chromosome 14 (BTA14). This genomic area includes the DGAT1 gene, which encodes acyl-CoA:diacylglycerol acyltransferase 1, the key enzyme of triglyceride biosynthesis. Genetic and biochemical studies led to the identification of the nonconservative DGAT1-K232A polymorphism as a causal mutation for the QTL. In addition to this, another polymorphism in the 5′-regulatory region of this gene, the DGAT1 variable number of tandem repeat (VNTR), also showed a strong association with milk fat percentage. This promoter VNTR polymorphism affects the number of potential Sp1 binding sites and therefore might have an impact on DGAT1 expression and also milk fat content. Hence, the DGAT1 VNTR polymorphism might be another causal mutation for the BTA14 QTL. However, evidence for Sp1 binding to this polymorphic site and for the capability of DGAT1 VNTR alleles to stimulate gene expression was lacking. In the current work Sp1-VNTR interactions were analyzed by EMSA. In addition, effects of DGAT1 VNTR alleles on gene expression were measured with reporter gene analyses. Conclusions from the results are that 1) the DGAT1 VNTR sequence is indeed a target for Sp1 binding; 2) DGAT1 VNTR alleles can stimulate gene expression in vitro and probably in vivo as well; and 3) although the stimulating effects of the different DGAT1 VNTR alleles did not show significant differences in vitro, their effects on transcription might be different in the chromatin context existing in vivo.

scholarly journals RTP801/REDD1 contributes to neuroinflammation severity and memory impairments in Alzheimer’s disease

2021 ◽  
Vol 12 (6) ◽  
Author(s):  
Leticia Pérez-Sisqués ◽  
Anna Sancho-Balsells ◽  
Júlia Solana-Balaguer ◽  
Genís Campoy-Campos ◽  
Marcel Vives-Isern ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Hippocampal Neurons ◽  
Mrna Levels ◽  
Spine Density ◽  
Memory Impairments ◽  
Protein Levels ◽  
Synaptic Markers ◽  
5Xfad Mice

AbstractRTP801/REDD1 is a stress-regulated protein whose upregulation is necessary and sufficient to trigger neuronal death. Its downregulation in Parkinson’s and Huntington’s disease models ameliorates the pathological phenotypes. In the context of Alzheimer’s disease (AD), the coding gene for RTP801, DDIT4, is responsive to Aβ and modulates its cytotoxicity in vitro. Also, RTP801 mRNA levels are increased in AD patients’ lymphocytes. However, the involvement of RTP801 in the pathophysiology of AD has not been yet tested. Here, we demonstrate that RTP801 levels are increased in postmortem hippocampal samples from AD patients. Interestingly, RTP801 protein levels correlated with both Braak and Thal stages of the disease and with GFAP expression. RTP801 levels are also upregulated in hippocampal synaptosomal fractions obtained from murine 5xFAD and rTg4510 mice models of the disease. A local RTP801 knockdown in the 5xFAD hippocampal neurons with shRNA-containing AAV particles ameliorates cognitive deficits in 7-month-old animals. Upon RTP801 silencing in the 5xFAD mice, no major changes were detected in hippocampal synaptic markers or spine density. Importantly, we found an unanticipated recovery of several gliosis hallmarks and inflammasome key proteins upon neuronal RTP801 downregulation in the 5xFAD mice. Altogether our results suggest that RTP801 could be a potential future target for theranostic studies since it could be a biomarker of neuroinflammation and neurotoxicity severity of the disease and, at the same time, a promising therapeutic target in the treatment of AD.

scholarly journals CREB Activation Mediates Plasticity in Cultured Hippocampal Neurons

1998 ◽  
Vol 6 (3) ◽  
pp. 1-7 ◽  
Author(s):  
Menahem Segal ◽  
Diane D. Murphy
Keyword(s):  
Cyclic Amp ◽  
Dendritic Spines ◽  
Hippocampal Neurons ◽  
Long Term Potentiation ◽  
Spine Density ◽  
Creb Phosphorylation ◽  
Molecular Events ◽  
Term Potentiation ◽  
Element Binding Protein ◽  
Responsive Element

Activation of cyclic AMP dependent kinase is believed to mediate slow onset, long-term potentiation (LTP) in central neurons. Cyclic- AMP activates a cascade of molecular events leading to phosphorylation of the nuclear cAMP responsive element binding protein (pCREB). Whereas a variety of stimuli lead to activation of CREB, the molecular processes downstream of CREB, which may be relevant to neuronal plasticity, are yet largely unknown. We have recently found that following exposure to estradiol, pCREB mediates the large increase in dendritic spine density in cultured rat hippocampal neurons. We now extend these observations to include other stimuli, such as bicuculline, that cause the formation of new dendritic spines. Such stimuli share with estradiol the same mechanism of action in that both require activity-dependent CREB phosphorylation. Our observations suggest that CREB phosphorylation is a necessary, but perhaps not sufficient, step in the process leading to the generation of new dendritic spines and perhaps to functional plasticity as well.

scholarly journals The Polyadenosine RNA Binding Protein ZC3H14 is Required in Mice for Proper Dendritic Spine Density

2020 ◽  
Author(s):  
Stephanie K. Jones ◽  
Jennifer Rha ◽  
Sarah Kim ◽  
Kevin J. Morris ◽  
Omotola F. Omotade ◽  
...  
Keyword(s):  
Dendritic Spine ◽  
Hippocampal Neurons ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
Spine Density ◽  
Dendritic Spine Density

AbstractZC3H14 (Zinc finger CysCysCysHis domain-containing protein 14), an evolutionarily conserved member of a class of tandem zinc finger (CCCH) polyadenosine (polyA) RNA binding proteins, is associated with a form of heritable, nonsyndromic autosomal recessive intellectual disability. Previous studies of a loss of function mouse model, Zc3h14Δex13/Δex13, provide evidence that ZC3H14 is essential for proper brain function, specifically for working memory. To expand on these findings, we analyzed the dendrites and dendritic spines of hippocampal neurons from Zc3h14Δex13/Δex13 mice, both in situ and in vitro. These studies reveal that loss of ZC3H14 is associated with a decrease in total spine density in hippocampal neurons in vitro as well as in the dentate gyrus of 5-month old mice analyzed in situ. This reduction in spine density in vitro results from a decrease in the number of mushroom-shaped spines, which is rescued by exogenous expression of ZC3H14. We next performed biochemical analyses of synaptosomes prepared from whole wild-type and Zc3h14Δex13/Δex13 mouse brains to determine if there are changes in steady state levels of postsynaptic proteins upon loss of ZC3H14. We found that ZC3H14 is present within synaptosomes and that a crucial postsynaptic protein, CaMKIIα, is significantly increased in these synaptosomal fractions upon loss of ZC3H14. Together, these results demonstrate that ZC3H14 is necessary for proper dendritic spine density in cultured hippocampal neurons and in some regions of the mouse brain. These findings provide insight into how a ubiquitously expressed RNA binding protein leads to neuronal-specific defects that result in brain dysfunction.

scholarly journals The 5-HT4 receptor interacts with adhesion molecule L1 to modulate morphogenic signaling in neurons

2021 ◽  
Vol 134 (4) ◽  
pp. jcs249193
Author(s):  
Simon Bennet Sonnenberg ◽  
Jonah Rauer ◽  
Christoph Göhr ◽  
Nataliya Gorinski ◽  
Sophie Kristin Schade ◽  
...  
Keyword(s):  
Adhesion Molecule ◽  
Dendritic Spines ◽  
Hippocampal Neurons ◽  
Serotonin Receptor ◽  
Resonance Energy Transfer ◽  
Resonance Energy ◽  
Mitogen Activated Protein Kinase ◽  
Physical Interaction ◽  
Dependent Manner

ABSTRACTMorphological remodeling of dendritic spines is critically involved in memory formation and depends on adhesion molecules. Serotonin receptors are also implicated in this remodeling, though the underlying mechanisms remain enigmatic. Here, we uncovered a signaling pathway involving the adhesion molecule L1CAM (L1) and serotonin receptor 5-HT4 (5-HT4R, encoded by HTR4). Using Förster resonance energy transfer (FRET) imaging, we demonstrated a physical interaction between 5-HT4R and L1, and found that 5-HT4R–L1 heterodimerization facilitates mitogen-activated protein kinase activation in a Gs-dependent manner. We also found that 5-HT4R–L1-mediated signaling is involved in G13-dependent modulation of cofilin-1 activity. In hippocampal neurons in vitro, the 5-HT4R–L1 pathway triggers maturation of dendritic spines. Thus, the 5-HT4R–L1 signaling module represents a previously unknown molecular pathway regulating synaptic remodeling.

scholarly journals Capicua Regulates Dendritic Morphogenesis Through Ets in Hippocampal Neurons in vitro

2021 ◽  
Vol 15 ◽  
Author(s):  
Keqin Li ◽  
Shuai Shao ◽  
Tongjie Ji ◽  
Min Liu ◽  
Lufeng Wang ◽  
...  
Keyword(s):  
Dendritic Spines ◽  
Hippocampal Neurons ◽  
Dendritic Growth ◽  
Dendrite Growth ◽  
Loss Of Function ◽  
Ht22 Cells ◽  
Dendritic Morphogenesis ◽  
Growth Loss ◽  
Main Period

Capicua (Cic), a transcriptional repressor frequently mutated in brain cancer oligodendroglioma, is highly expressed in adult neurons. However, its function in the dendritic growth of neurons in the hippocampus remains poorly understood. Here, we confirmed that Cic was expressed in hippocampal neurons during the main period of dendritogenesis, suggesting that Cic has a function in dendrite growth. Loss-of-function and gain-of function assays indicated that Cic plays a central role in the inhibition of dendritic morphogenesis and dendritic spines in vitro. Further studies showed that overexpression of Cic reduced the expression of Ets in HT22 cells, while in vitro knockdown of Cic in hippocampal neurons significantly elevated the expression of Ets. These results suggest that Cic may negatively control dendrite growth through Ets, which was confirmed by ShRNA knockdown of either Etv4 or Etv5 abolishing the phenotype of Cic knockdown in cultured neurons. Taken together, our results suggest that Cic inhibits dendritic morphogenesis and the growth of dendritic spines through Ets.

scholarly journals Perinatal Exposure of Bisphenol A Differently Affects Dendritic Spines of Male and Female Grown-Up Adult Hippocampal Neurons

2021 ◽  
Vol 15 ◽  
Author(s):  
Suguru Kawato ◽  
Mari Ogiue-Ikeda ◽  
Mika Soma ◽  
Hinako Yoshino ◽  
Toshihiro Kominami ◽  
...  
Keyword(s):  
Bisphenol A ◽  
Estrous Cycle ◽  
Dendritic Spines ◽  
Hippocampal Neurons ◽  
Lucifer Yellow ◽  
Hippocampal Slices ◽  
Perinatal Exposure ◽  
Spine Density ◽  
Large Head ◽  
Moderate Change

Perinatal exposure to Bisphenol A (BPA) at a very low dose may modulate the development of synapses of the hippocampus during growth to adulthood. Here, we demonstrate that perinatal exposure to 30 μg BPA/kg per mother’s body weight/day significantly altered the dendritic spines of the grownup rat hippocampus. The density of the spine was analyzed by imaging of Lucifer Yellow-injected CA1 glutamatergic neurons in adult hippocampal slices. In offspring 3-month male hippocampus, the total spine density was significantly decreased by BPA exposure from 2.26 spines/μm (control, no BPA exposure) to 1.96 spines/μm (BPA exposure). BPA exposure considerably changed the normal 4-day estrous cycle of offspring 3-month females, resulting in a 4∼5 day estrous cycle with 2-day estrus stages in most of the subjects. In the offspring 3-month female hippocampus, the total spine density was significantly increased by BPA exposure at estrus stage from 2.04 spines/μm (control) to 2.25 spines/μm (BPA exposure). On the other hand, the total spine density at the proestrus stage was moderately decreased from 2.33 spines/μm (control) to 2.19 spines/μm (BPA exposure). Thus, after the perinatal exposure to BPA, the total spine density in males became lower than that in females. Concerning the BPA effect on the morphology of spines, the large-head spine was significantly changed with its significant decrease in males and moderate change in females.

scholarly journals Pannexin 1 regulates spiny protrusion dynamics in cortical neurons

2020 ◽  
Author(s):  
Juan C. Sanchez-Arias ◽  
Rebecca C. Candlish ◽  
Leigh Anne Swayne
Keyword(s):  
Dendritic Spines ◽  
Dendritic Spine ◽  
Cortical Neurons ◽  
Neuronal Networks ◽  
Local Environment ◽  
Spine Density ◽  
Pannexin 1 ◽  
Developing Neurons ◽  
The Impact

AbstractThe integration of neurons into networks relies on the formation of dendritic spines. These specialized structures arise from dynamic filopodia-like spiny protrusions. Recently, it was discovered that cortical neurons lacking the channel protein Pannexin 1 (Panx1) exhibited larger and more complicated neuronal networks, as well as, higher dendritic spine densities. Here, we expanded on those findings to investigate whether the increase in dendritic spine density associated with lack of Panx1 was due to differences in the rates of spine dynamics. Using a fluorescent membrane tag (mCherry-CD9-10) to visualize spiny protrusions in developing neurons (at 10 days-in-vitro, DIV10) we confirmed that lack of Panx1 leads to higher spiny protrusion density while transient transfection of Panx1 leads to decreased spiny protrusion density. To quantify the impact of Panx1 expression on spiny protrusion formation, elimination, and motility, we used live cell imaging in DIV10 neurons (1 frame every 5 seconds for 10 minutes). We discovered, that at DIV10, lack of Panx1 KO stabilized spiny protrusions. Notably, re-expression of Panx1 in Panx1 knockout neurons resulted in a significant increase in spiny protrusion motility and turnover. In summary, these new data revealed that Panx1 regulates the development of dendritic spines by controlling protrusion dynamics.Significance statementCells in the brain form intricate and specialized networks - neuronal networks - in charge of processing sensations, executing movement commands, and storing memories. To do this, brain cells extend microscopic protrusions - spiny protrusions - which are highly dynamic and survey the local environment to contact other cells. Those contact sites are known as synapses and undergo further stabilization and maturation establishing the function and efficiency of neuronal networks. Our work shows that removal of Panx1 increases the stability and decreases the turnover of spiny protrusion on young neurons.

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