Figure 1
EFhd2 expression in adult mouse brain determined by lacZ reporter gene expression. (A) Replacement of the murine efhd2 locus by a lacZ reporter gene cassette. E1-4: Exons. Black: coding regions in exons. (B) Lysates of brains of wild-type (+/+), heterozygous (+/2) or EFhd2-deficient mice (2/2) were subjected to western blot analysis with antibodies indicated on the right. (C) Whole mount lacZ reporter gene staining of brains of adult mice. (D) Coronal sections of anterior and posterior parts of whole mount stained brains from adult EFhd2 +/+ , EFhd2 +/2 andEFhd2 2/2 mice. doi:10.1371/journal.pone.0103976.g001
Source publication
Swiprosin-1/EFhd2 (EFhd2) is a cytoskeletal Ca2+ sensor protein strongly expressed in the brain. It has been shown to interact with mutant tau, which can promote neurodegeneration, but nothing is known about the physiological function of EFhd2 in the nervous system. To elucidate this question, we analyzed EFhd2-/-/lacZ reporter mice and showed that...
Contexts in source publication
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... determine the expression of EFhd2 in the adult brain we utilized an EFhd2 2/2 knockout/lacZ knock-in mouse strain generated in our laboratory [14]. In heterozygous animals (EFhd2 +/2 ), one efhd2 allele is replaced by a lacZ reporter gene (Fig. 1A). The lacZ reporter gene downstream of the efhd2 promoter, resulting in b-galactosidase expression, indicates efhd2 mRNA expression, which we have shown to be strong compared to other tissues [3]. Hence, EFhd2 2/+ and EFhd2 2/2 mice express b-galactosidase in the adult brain, while protein levels of EFhd2 are reduced correspondingly ...
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... gene (Fig. 1A). The lacZ reporter gene downstream of the efhd2 promoter, resulting in b-galactosidase expression, indicates efhd2 mRNA expression, which we have shown to be strong compared to other tissues [3]. Hence, EFhd2 2/+ and EFhd2 2/2 mice express b-galactosidase in the adult brain, while protein levels of EFhd2 are reduced correspondingly (Fig. 1B). Whole mount staining revealed strong b-galactosidase activity in the forebrain (Fig. 1C). To determine efhd2 expression in more detail, we sectioned whole mount stained adult mouse brains coronally Fig. 1D). Prominent dose-dependent b-galactosidase activity indic- ative of efhd2 promoter activity was detected in the deeper layers of ...
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... expression, indicates efhd2 mRNA expression, which we have shown to be strong compared to other tissues [3]. Hence, EFhd2 2/+ and EFhd2 2/2 mice express b-galactosidase in the adult brain, while protein levels of EFhd2 are reduced correspondingly (Fig. 1B). Whole mount staining revealed strong b-galactosidase activity in the forebrain (Fig. 1C). To determine efhd2 expression in more detail, we sectioned whole mount stained adult mouse brains coronally Fig. 1D). Prominent dose-dependent b-galactosidase activity indic- ative of efhd2 promoter activity was detected in the deeper layers of the cortex (IV, V, and VI), as well as the dentate gyrus, the CA1 and CA2 areas of the ...
Context 4
... Hence, EFhd2 2/+ and EFhd2 2/2 mice express b-galactosidase in the adult brain, while protein levels of EFhd2 are reduced correspondingly (Fig. 1B). Whole mount staining revealed strong b-galactosidase activity in the forebrain (Fig. 1C). To determine efhd2 expression in more detail, we sectioned whole mount stained adult mouse brains coronally Fig. 1D). Prominent dose-dependent b-galactosidase activity indic- ative of efhd2 promoter activity was detected in the deeper layers of the cortex (IV, V, and VI), as well as the dentate gyrus, the CA1 and CA2 areas of the hippocampus. b-galactosidase activity was also observed in the thalamus and the olfactory bulb (Fig. ...
Context 5
... adult mouse brains coronally Fig. 1D). Prominent dose-dependent b-galactosidase activity indic- ative of efhd2 promoter activity was detected in the deeper layers of the cortex (IV, V, and VI), as well as the dentate gyrus, the CA1 and CA2 areas of the hippocampus. b-galactosidase activity was also observed in the thalamus and the olfactory bulb (Fig. ...
Citations
... EFHD2 is broadly expressed in various cell types, with particularly high expression in neurons 12 . The studies of the pathological role of EFHD2 therefore have focused on behavioral pathologies, neurological disorders, and neurodegenerative diseases 12,[15][16][17] , highlighting the role of EFHD2 in regulating the membrane-cytoplasm trafficking of membrane-associated proteins. Our previous study showed that EFHD2 can interact with phosphorylated IFN-γR2 to promote IFN-γR2 trafficking from Golgi to cell membrane of macrophages upon intracellular bacterial infection, which facilitates subsequent IFN-γ signaling in innate response 18 . ...
TNF acts as one pathogenic driver for inducing intestinal epithelial cell (IEC) death and substantial intestinal inflammation. How the IEC death is regulated to physiologically prevent intestinal inflammation needs further investigation. Here, we report that EF-hand domain-containing protein D2 (EFHD2), highly expressed in normal intestine tissues but decreased in intestinal biopsy samples of ulcerative colitis patients, protects intestinal epithelium from TNF-induced IEC apoptosis. EFHD2 inhibits TNF-induced apoptosis in primary IECs and intestinal organoids (enteroids). Mice deficient of Efhd2 in IECs exhibit excessive IEC death and exacerbated experimental colitis. Mechanistically, EFHD2 interacts with Cofilin and suppresses Cofilin phosphorylation, thus blocking TNF receptor I (TNFR1) internalization to inhibit IEC apoptosis and consequently protecting intestine from inflammation. Our findings deepen the understanding of EFHD2 as the key regulator of membrane receptor trafficking, providing insight into death receptor signals and autoinflammatory diseases.
... EFhd2 is a cytoskeletal Ca 2+ -sensor protein localized in the cytosol (Purohit et al., 2014). It was first detected in human CD8+ lymphocytes, where it stabilizes actin filaments by regulating the accessibility of F-actin to cofilin, which depolymerizes the F-actin (Vuadens et al., 2004;Huh et al., 2013). ...
EF-hand proteins, which contain a Ca²⁺-binding EF-hand motif, are involved in regulating diverse cellular functions. Ca²⁺ binding induces conformational changes that modulate the activities of EF-hand proteins. Moreover, these proteins occasionally modify their activities by coordinating metals other than Ca²⁺, including Mg²⁺, Pb²⁺ and Zn²⁺, within their EF-hands. EFhd1 and EFhd2 are homologous EF-hand proteins with similar structures. Although separately localized within cells, both are actin-binding proteins that modulate F-actin rearrangement through Ca²⁺-independent actin-binding and Ca²⁺-dependent actin-bundling activity. Although Ca²⁺ is known to affect the activities of EFhd1 and EFhd2, it is not known whether their actin-related activities are affected by other metals. Here, the crystal structures of the EFhd1 and EFhd2 core domains coordinating Zn²⁺ ions within their EF-hands are reported. The presence of Zn²⁺ within EFhd1 and EFhd2 was confirmed by analyzing anomalous signals and the difference between anomalous signals using data collected at the peak positions as well as low-energy remote positions at the Zn K-edge. EFhd1 and EFhd2 were also found to exhibit Zn²⁺-independent actin-binding and Zn²⁺-dependent actin-bundling activity. This suggests the actin-related activities of EFhd1 and EFhd2 could be regulated by Zn²⁺ as well as Ca²⁺.
... Studies on physiological functions of swiprosin-1/EFHD2 have shown that in neurons, swiprosin-1 is involved in synapses and intracellular transport [10]. As swiprosin-1 is a Ca 2+ binding protein and highly expressed in brain, it is reported to serve major functions in the brain [11]. Owing to its influence on neuronal activity, swiprosin-1 has been shown to affect behavior and locomotor activity [12]. ...
... However, the presence of EFHD2 inhibited kinesin (KIF5A) mediated microtubule (MT) gliding, whereas absence of EFHD2 promoted it in neurons. Therefore, it was suggested that EFHD2 might slowdown the kinesinmediated transport in neurons due to the diminished kinesin-MT interaction [11]. ...
... This indicates the possible role of EFHD2 in cognitive processes within the frontal cortex [3,90]. Moreover, the regulation of intracellular calcium responses [15], microtubule transport functions [11] and actin dynamics [16,23] are found to be dependent on the expression of EFHD2 in a cell type-specific manner. It has been reported that EFHD2 expression is lowered in human frontal cortex tissue of patients with Alzheimer's disease, Pick disease, as well as frontotemporal dementia with tau mutations (FTLD-tau) as compared to control nondemented individuals. ...
Swiprosin-1 or EFHD2, is a Ca²⁺ binding actin protein and its expression has been shown to be distinct in various cell types. The expression of swiprosin-1 is upregulated during the activation of immune cells, epithelial and endothelial cells. The expression of swiprosin-1 is regulated by diverse signaling pathways that are contingent upon the specific type of cells. The aim of this review is to summarize and provide an overview of the role of swiprosin-1 in pathophysiological conditions of cancers, cardiovascular diseases, diabetic nephropathy, neuropsychiatric diseases, and in the process of inflammation, immune response, and inflammatory diseases. Novel approaches for the targeting of swiprosin-1 as a biomarker in the early detection and prevention of various development of chronic diseases are also explored.
... EFHD2 is responsible for the interaction with mutant tau in brain extracts of JNPL3 mice in vitro (Vega et al. 2008) and also acts as putative cytoskeletal adaptor interacting with the microtubuleassociated protein TAU (Ferrer-Acosta et al. 2013). Previous studies shown that EFHD2 is highly expressed in the central nervous system and knockout of EFHD2 could impair neurogenesis of DG in EFHD2 −/− mice (Purohit et al. 2014;Regensburger et al. 2018). Although EFHD2 expression has been proved to significantly increase in AD mouse model and postmortem studies (Ferrer-Acosta et al. 2013;Vega 2016), its function in AD and memory consolidation was still unknown. ...
Memory formation and consolidation necessitate gene expression and new protein synthesis. MicroRNAs (miRNAs), a family of small noncoding RNAs that inhibit target gene mRNA expression, are involved in new memory formation. In this study, elevated miR-126a-3p (miR-126) levels were found to contribute to the consolidation of contextual fear memory. Using different commonly mined algorithms and luciferase reporter assay, we found two Alzheimer’s disease (AD)-related proteins, namely EFHD2 and BACE1, but not ADAM9, were the targets downregulated by miR-126 after CFC training. Moreover, we indicated that upregulated miR-126 could promote the formation of contextual fear memory by modulating its target EFHD2. Finally, we demonstrated that miR-126 overexpression in dentate gyrus of hippocampus could reduce Aβ plaque area and neuroinflammation, as well as rescue the hippocampal memory deficits in APP/PS1 mice. This study adds to the growing body of evidence for the role of miRNAs in memory formation and demonstrates the implication of EFHD2 protein regulated by miR-126 in the adult brain.
... EFhd2 is widely expressed in most organs with predominant levels in the central nervous system (CNS) (Vega et al., 2008). In particular, it is abundant in forebrain regions such as the hippocampus, frontal cortex, and olfactory bulb with lower levels in the cerebellum and brain stem (Purohit et al., 2014). Reportedly, EFhd2 is mainly expressed in the grey matter where it localizes to the somatodendritic synaptic compartments Purohit et al., 2014). ...
... In particular, it is abundant in forebrain regions such as the hippocampus, frontal cortex, and olfactory bulb with lower levels in the cerebellum and brain stem (Purohit et al., 2014). Reportedly, EFhd2 is mainly expressed in the grey matter where it localizes to the somatodendritic synaptic compartments Purohit et al., 2014). However, the biological role of EFhd2 is still unclear. ...
... Efhd2 (−/−) mice develop without gross anatomical, developmental, or morphological anomalies, despite impaired dendritic morphology in the CNS (Purohit et al., 2014;Regensburger et al., 2018;Rodriguez-Cruz, 2014). Other studies suggested that EFhd2 proteins regulate the behavioral response to alcohol and drug addiction (Kogias et al., 2019). ...
EFhd2 is a conserved calcium‐binding protein that is highly expressed in the central nervous system. We have shown that EFhd2 interacts with tau protein, a key pathological hallmark in Alzheimer's disease and related dementias. However, EFhd2’s physiological and pathological functions in the brain are still poorly understood. To gain insights into its physiological function, we identified proteins that co‐immunoprecipitated with EFhd2 from mouse forebrain and hindbrain, using tandem mass spectrometry (MS). In addition, quantitative mass spectrometry was used to detect protein abundance changes due to the deletion of the Efhd2 gene in mouse forebrain and hindbrain regions. Our data show that mouse EFhd2 is associated with cytoskeleton components, vesicle trafficking modulators, cellular stress response‐regulating proteins, and metabolic proteins. Moreover, proteins associated with the cytoskeleton, vesicular transport, calcium signaling, stress response, and metabolic pathways showed differential abundance in Efhd2 (−/−) mice. This study presents, for the first time, an EFhd2 brain interactome that it is associated with different cellular and molecular processes. These findings will help prioritize further studies to investigate the mechanisms by which EFhd2 modulates these processes in physiological and pathological conditions of the nervous system.
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... 3 EFHD2 regulates axonal transport, 4 axonal generation, 3 actin remodeling, 5 and synaptic plasticity. 4 Much research has been conducted to investigate the involvement of this protein in various neurological diseases. Previous studies have reported that EFHD2 is altered in Alzheimer's disease, [6][7][8][9] Parkinson's disease, 10 suicide, 11 and alcohol dependence. ...
... 15 Intracellular Ca 2þ levels control dopamine receptor function and maintain neurotransmitter exocytosis during stimulation. EFHD2 is a Ca 2þ sensor protein that exists in neuronal axons and participates in actin-mediated transport in neurons, 4 and may be closely related to SCZ. Furthermore, synaptic dysfunction is closely related to SCZ, and EFHD2 is involved in the transport of vesicles containing synaptic proteins, and may be a synaptic protein itself. ...
... EFHD2 expression can promote synaptic development in neurons and regulate synaptic plasticity. 4 The microtubuleassociated protein (MAP) family has also been shown to be a therapeutic target for SCZ. 15 Axonal transport requires the participation of MAP, and EFHD2 affects axonal transport through MAP. ...
Objective
Schizophrenia is a severe neurodevelopmental disorder with a complex genetic and environmental etiology. The gene encoding EF-hand domain-containing protein D2 ( EFHD2) may be a genetic risk locus for schizophrenia.
Methods
We genotyped four EFHD2 single-nucleotide polymorphisms (281 schizophrenia cases [SCZ], 321 controls) from northern Chinese Han individuals using Sanger sequencing and polymerase chain reaction-restriction fragment length polymorphism analysis. Differences existed in genotype, allele, and haplotype frequency distributions between SCZ and control groups.
Results
The rs2473357 genotype and allele frequency distributions differed between SCZ and controls; however, this difference disappeared after Bonferroni correction. Differences in rs2473357 genotype and allele frequency distributions between SCZ and controls were more pronounced in men than in women. The G allele increased schizophrenia risk (odds ratio = 1.807, 95% confidence interval = 1.164–2.803). Among six haplotypes (G–, A–, G-insC, A-C, G-C, and G-T), the G– haplotype frequency distribution differed between SCZ and controls in women; the A-C and G-C haplotype frequency distributions differed between SCZ and controls in men.
Conclusions
EFHD2 may be involved in schizophrenia. Sex differences in EFHD2 genotype and allele frequency distributions existed among schizophrenia patients. Further research is needed to determine the role of EFHD2 in schizophrenia.
... EFhd2 binds directly to F-actin where it controls its turnover (Huh et al., 2013;Kwon et al., 2013;Mielenz and Gunn-Moore, 2016), suggesting that it might affect synaptic plasticity (Gu et al., 2010). EFhd2 is widely expressed in the human and mice brain, with highest expression in the cortex and hippocampus Purohit et al., 2014). In the brain, it is found in neurons, particularly in axons, dendrites and synaptic complexes Purohit et al., 2014). ...
... EFhd2 is widely expressed in the human and mice brain, with highest expression in the cortex and hippocampus Purohit et al., 2014). In the brain, it is found in neurons, particularly in axons, dendrites and synaptic complexes Purohit et al., 2014). In neurons EFhd2 controls axonal transport and kinesin-mediated microtubule gliding (Purohit et al., 2014), as well as pre-synaptic density composition . ...
... In the brain, it is found in neurons, particularly in axons, dendrites and synaptic complexes Purohit et al., 2014). In neurons EFhd2 controls axonal transport and kinesin-mediated microtubule gliding (Purohit et al., 2014), as well as pre-synaptic density composition . Maclaren and Sikela (2005) compared inbred short sleep (ISS) with inbred long sleep (ILS) mice for their gene expression profiles and the sensitivity to the sedative effects of alcohol. ...
While the majority of the regular consumers of alcohol controls their consumption well over life span and even takes instrumentalization benefits from it, a minority, but yet high total number of users develops an alcohol addiction. It has long been known that particular personality types are more addiction prone than others. Here we review recent progress in the understanding of neurobiological pathways that determine personality and facilitate drug abuse. Novel approaches to characterize personality traits leading to addiction proneness in social settings in mice are discussed. A common genetic and neurobiological base for the behavioural traits of sensation seeking or a depressed phenotype and escalating alcohol consumption are reviewed. Furthermore, recent progress on how social and cognitive factors, including impulsivity and decision making, act at brain level to make an individual more vulnerable to alcohol abuse, are discussed. Altogether, this review provides an update on brain mechanisms underlying a broad spectrum of personality traits that make an individual more prone to alcohol and drug abuse and addiction.
... Cofilin is needed for the depolymerization of F-actin [2]. Expression of swiprosin-1 has already been identified in 2 of 13 lymphocytes, B-cells, mast cells, T-cells, neurons, podocytes, and cardiomyocytes [3][4][5][6][7][8][9]. Furthermore, a drosophila-specific homologue of human swiprosin-1 participates in skeletal muscle formation [10]. ...
Swiprosin-1 (EFhD2) is a molecule that triggers structural adaptation of isolated adult rat cardiomyocytes to cell culture conditions by initiating a process known as cell spreading. This process mimics central aspects of cardiac remodeling, as it occurs subsequent to myocardial infarction. However, expression of swiprosin-1 in cardiac tissue and its regulation in vivo has not yet been addressed. The expression of swiprosin-1 was analyzed in mice, rat, and pig hearts undergoing myocardial infarction or ischemia/reperfusion with or without cardiac protection by ischemic pre- and postconditioning. In mouse hearts, swiprosin-1 protein expression was increased after 4 and 7 days in myocardial infarct areas specifically in cardiomyocytes as verified by immunoblotting and histology. In rat hearts, swiprosin-1 mRNA expression was induced within 7 days after ischemia/reperfusion but this induction was abrogated by conditioning. As in cultured cardiomyocytes, the expression of swiprosin-1 was associated with a coinduction of arrestin-2, suggesting a common mechanism of regulation. Rno-miR-32-3p and rno-miR-34c-3p were associated with the regulation pattern of both molecules. Moreover, induction of swiprosin-1 and ssc-miR-34c was also confirmed in the infarct zone of pigs. In summary, our data show that up-regulation of swiprosin-1 appears in the postischemic heart during cardiac remodeling and repair in different species.
... It consists of a distorted N-terminus, two functional EF hand domains and a coiled-coil domain that mediates its dimerization in a Ca 2+ -dependent manner, leading to the bundling of F-Actin filaments (Dütting, Brachs, & Mielenz, 2011;Huh et al., 2013;Kwon et al., 2013;Park et al., 2017Park et al., , 2016. It functions as a Ca 2+ sensor protein (Hagen et al., 2012) and its expression is up-regulated in the adult brain (Purohit et al., 2014). EFhd2 inhibits kinesin-mediated transport along microtubules in vitro and in primary neurons (Purohit et al., 2014). ...
... It functions as a Ca 2+ sensor protein (Hagen et al., 2012) and its expression is up-regulated in the adult brain (Purohit et al., 2014). EFhd2 inhibits kinesin-mediated transport along microtubules in vitro and in primary neurons (Purohit et al., 2014). It has been documented to be involved in various neurobiological functions, such pre-synapse formation (Borger, Herrmann, Mann, Spires-Jones, & Gunn-Moore, 2014;Hornbruch-Freitag, Griemert, Buttgereit, & Renkawitz-Pohl, 2011), neurogenesis (Hornbruch-Freitag et al., 2011), cortical development and neurodegenerative diseases (Regensburger et al., 2018;Vega et al., 2008). ...
Psychostimulants are widely abused drugs that may cause addiction in vulnerable individuals. While the reward circuitry of the brain is involved in addiction establishment, various pathways in the brain may provide protection at the molecular level that limits the acute and chronic effects of drugs. These targets may be used for strategies designed to prevent and treat addiction. Swiprosin‐1/EFhd2 is a Ca2+‐binding cytoskeletal adaptor protein involved in sensation seeking behaviour, anxiety and alcohol addiction. Here, we tested how EFhd2 contributes to the physiological and behavioural effects of the psychostimulant drugs methamphetamine (METH) and cocaine. An in‐vivo microdialysis study in EFhd2 knock out (KO) mice revealed that EFhd2 controls METH‐ and cocaine‐induced changes in extracellular dopamine (DA), serotonin and noradrenaline levels through different mechanisms in the nucleus accumbens (NAc) and prefrontal cortex (PFC). Electrophysiological recordings in a slice preparation showed that a lack of EFhd2 increases dopaminergic neuronal activity in the ventral tegmental area and increases the sensitivity of neurons to stimulation. We report a role of EFhd2 in METH‐induced locomotor activation and in the conditioned locomotor effects. No role, however, was observed in the establishment of METH‐ or cocaine‐induced conditioned place preference. These findings may suggest that EFhd2 modulates the activity of the dopaminergic system and the neurochemical effects of METH and cocaine, which translate into a modulation of the behavioural effects of these drugs at the level of the acute and conditioned locomotor activity.
... Moreover, EF hand containing domain 2 (EFhd2), a novel calcium sensor protein has been implicated in numerous neurodegenerative disorders. EFhd2 interacts with different neuropathological proteins including mutant tau proteins implicated in AD, C9orf72 involved in pathogenesis of ALS and leucine rich repeat kinase 2 (LRRK2) implicated in PD and thus promote neurodegeneration [37,38]. Association of EFhd2 with neuropathological tau proteins has been confirmed in JNPL3 mouse brain and AD brains [39]. ...
Neurodegenerative disorders like Alzheimer's disease, Huntington's disease, Parkinson's disease, spinocerebellar ataxias, amyotrophic lateral sclerosis, frontotemporal dementia to prion diseases, Friedreich's ataxia, hereditary spastic paraplegia and optic atrophy type 1, and behavior disorders like neuropsychiatric, hyperactivity and autism spectrum disorders are closely associated with neurobiological deficits. Brain derived neurotrophic factor (BDNF) is an extensively studied neurotrophin. BDNF is essential for neuronal genesis, differentiation, survival, growth, plasticity, synaptic viability and transmission. BDNF has emerged as a promising target for regulating synaptic activity and plasticity. An overview of effects and mechanisms of the natural products targeting BDNF is described. This review is an attempt to enumerate the effects of various natural products on BDNF as a novel therapeutic approach for neurodegenerative and neuropsychiatric disorders.
