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Progress on the roles of MEF2C in neuropsychiatric diseases

Progress on the roles of MEF2C in neuropsychiatric diseases Myocyte Enhancer Factor 2 C (MEF2C), one of the transcription factors of the MADS-BOX family, is involved in embry- onic brain development, neuronal formation and differentiation, as well as in the growth and pruning of axons and dendrites. MEF2C is also involved in the development of various neuropsychiatric disorders, such as autism spectrum disorders (ASD), epilepsy, schizophrenia and Alzheimer’s disease (AD). Here, we review the relationship between MEF2C and neuropsychiatric disorders, and provide further insights into the mechanism of these diseases. Keywords: MEF2C, Transcription factor, Synapse, Neurodevelopment, Neuropsychiatric disease well as recruitment of cofactors. TAD is involved in the Introduction recruitment of cofactors, including co-activators such MEF2C is an important member of the myocyte enhancer as histone acetyltransferase p300 and cAMP-response factor 2 (MEF2). MEF2 is a subfamily of the MADS-BOX element-binding protein-binding protein (CBP), or co- (MCM-1-agamous-deficiens-serum response factor) repressors such as class II histone deacetylases (HDACs), family of transcriptional regulatory factors, which play that regulates transcription [4]. Besides, through alter- essential roles in embryogenesis and epigenetic modifica - native splicing at the mRNA level [85], and post-trans- tions that control gene expressions during development lational modifications such as phosphorylation or and throughout adulthood [23]. The MEF2 family consist dephosphorylation [11], acetylation [3], sumoylation [63] of four members MEF2A, MEF2B, MEF2C and MEF2D. and S-nitrosylation [52], MEF2C appears various expres- MEF2C is the earliest expressed MEF2 isomer in the tel- sion pattern and transactivation functions. In addition, encephalon of mouse embryos, and is the most expressed MEF2C mediates physiological processes such as cardiac in the cerebral cortex of postnatal and adult mouse morphogenesis, angiogenesis, muscle cell differentia - brains. Therefore, it is critical for proper nervous system tion, bone development, and neural or lymphatic system development and functional maintenance [4]. development [44]. The human MEF2C gene is located in  the  chromo - In the absence of external stimulation, the MEF2 pro- some 5q14.3  region and its protein consists of five core tein in the central nervous system binds and inactivates domains; MADS domain, MEF2 domain, transcriptional target genes. Various stimuli, such as depolarization, activation domains 1 (TAD1) and 2 (TAD2), as well as the neurotrophin or synaptic stimulation (e.g., glutamate nuclear localization signal (NLS). The MADS and MEF2 synaptic Reelin) activates neurons, thereby triggering cal- domains mediate MEF2C dimerization, DNA binding as cium signaling responses, including calmodulin-depend- ent protein kinase (CaMK), leading to phosphorylation *Correspondence: yongxiang_Zhao@126.com of class IIa HDACs. These phosphorylation events cause National Center for International Research of Bio-Targeting Theranostics, to a nuclear output of HDACs, and their subsequent Guangxi Key Laboratory of Bio-Targeting Theranostics, Collaborative removal from the MEF2 target gene, allowing the recruit- Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Medical University, Nanning 530021, Guangxi, China ment of co-activators [46]. MiR-124 and miR-9 have been Full list of author information is available at the end of the article shown to co-inhibit HDACs 5 expressions, which activate © The Author(s) 2022. 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The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Zhang and Zhao Molecular Brain (2022) 15:8 Page 2 of 11 the neuron membrane glycoprotein, GPM6A, a MEF2C Alzheimer’s disease target gene. These activities promote the development of AD is a neurodegenerative disease that is associated axons in primary neurons (Fig. 1) [25]. with progressive cognitive and memory deterioration. In addition, protein phosphatase 2B or calcineurin Inflammation is involved in AD pathogenesis [19]. As can directly dephosphorylate MEF2, thereby affecting the first and main immune defense component of central its affinity towards target DNA sequences, and promot - nervous system (CNS), microglia act as macrophages, ing its transcription activities [43]. MEF2C is involved clearing metabolites and necrotic cells in the brain in regulation of neuronal migration, activity-dependent through phagocytosis. However, continuous activation cell survival, neuronal differentiation, axon guidance and of microglia leads to the secretion of various neurotoxic pruning, dendritic formation and remodeling, as well as substances, which play an important role in AD devel- in synaptic development and neuronal excitability [37, opment [54]. For instance, when interferon-β (IFN-β), a 39, 84]. In the last decade, human genome-wide asso- pro-inflammatory cytokine related to brain ageing, was ciation study (GWAS) and genome sequencing of large injected into the cerebrospinal fluid of young wild type patient samples revealed that MEF2C is a candidate risk (WT) or MEF2C-knock out (MEF2C-KO) mice, sup- gene for various neuropsychiatric disorders, such as AD pressed social interaction outcomes were observed in [67], ASD [83], schizophrenia [47], bipolar disorder [50], the MEF2C-KO mice, compared to WT mice. Following major depression [28], attention deficit and hyperactiv - immune activations, the expressions of pro-inflammatory ity disorder [62], epilepsy [80] or Parkinson’s disease [59]. chemokines (CCL2 and CCL5) and cytokines (IL-1b We review recent findings on MEF2C as well as its role in and TNF) in MEF2C-KO mice were significantly higher some neuropsychiatric diseases and provide theoretical than in WT mice. uTh s MEF2C enhances the resil - and detailed insights that will inform future studies. ience of microglia to immune challenges and promotes Fig. 1 The functional regulation model of MEF2C in neuronal cells, where MEF2C is particularly important for the regulation of dendritic spines. The blue italics are MEF2C-associated psychoneurotic disorders Zhang and Zhao Molecular Brain (2022) 15:8 Page 3 of 11 homeostasis in pre-inflammatory states. Type I inter - rs190982 polymorphism and AD (OR = 0.885, 95% feron (IFN-I) accumulation down-regulates the MEF2C CI = 0.811 ~ 0.966) has been reported [10]. Based on in microglia, leading to excess microglia responses analyses of pathological data on AD, among 22 genetic under pro-inflammatory environments of AD or aging variations of AD, the rs190982 variation in MEF2C brains, and aggravates cognitive impairment and disease gene, was the only one that was found to exert signifi - pathology [20]. As reported by Xue et al., the suppressed cant effects on cognitive functions [42]. However, other MEF2C nuclear translocation as an early and prominent studies have reported the negative association [8, 66]. A microglial phenotype in a mouse model of brain amy- genome-wide association studies (GWAS) meta-analysis loidosis (5 × FAD mice) implies an association between involving a Taiwanese population of China did not reveal MEF2C deregulation and microglial phenotypes in AD- positive association between MEF2Crs190982 polymor- relative settings. Although they did not report the down- phism and AD, however, there were interactions between regulation of MEF2C mRNA copies in the microglia of MEF2Crs9293506 and cognitive aging. The risk for cog - 5 × FAD mice, upregulated MEF2C in microglia after nitive aging in carriers with TC genotypes of MEF2C anti-IFNAR antibody administration implies a potential rs9293506 was 2.79 times higher than that of those with strategy for improving microglial elasticity by upregu- the CC genotype [41]. These variations may be attributed lation of MEF2C [77]. A significant decrease in MEF2C to genetic heterogeneities among different ethnic groups, mRNA levels in leukocytes of AD patients has been such as differences in minor alleles, different frequencies positively correlated with total scores of Mini-Mental of secondary alleles or heterogeneity of potential genetic State Examination (MMSE). Therefore, expression levels structures. of MEF2C mRNA in leukocytes may not only be a bio- In a 2013 meta-analysis, Lambert et  al. found a marker for AD diagnosis, but be a potential biomarker genome-wide significant association between MEF2C for early detection of cognitive decline, such as mild cog- and AD [35], however, the significant association was nitive impairment (MCI) [60]. not replicated in a larger sample study performed in 2019 In addition, MEF2C plays an important role in amy- [34]. Moreover, Jansen et  al. were unable to establish an loid-protein precursor protein (APP) -mediated anti- association between MEF2C and AD in a large sample apoptotic neuroprotection [12]. MEF2C is a potential study from the UK Biobank (UKB) [29]. regulator of APP proteolysis, during which amyloid beta Although GWAS have been a valuable platform for (Aβ), a central factor in AD initiation, is produced [13]. identifying candidates for disease-related genetic vari- These findings elucidate on pathways involved in oligo - ants, the confirmed risk loci for AD only explains a small meric Aβ-potentiated microglial activation. portion of AD heritability (Table  1). To address some of Methyl CpG binding protein 2 (MeCP2; an impor- the limitations encountered by univariate SNP-based tant transcriptional inhibitor) levels have been shown to analyses, advanced methods were  developed to examine be increased in the cerebral cortex and hippocampus of SNPs in aggregate. The aggregated SNP approach may AD patients. MeCP2-mediated MEF2C inhibition may reduce the total number of tests performed and increase be associated with cognitive decline in AD [33]. Inter- power by exploiting linkage disequilibrium (LD) across estingly, other studies have reported a significant corre - multiple SNPS [76]. It hypothesized that variations in lation between cognitive functions and seasons among entire gene regions, rather than isolated single SNPS, the elderly. There is a 4-year difference in cognitive func - play a role in cognitive decline [48]. Other strategies for tions between summer and autumn, compared to winter improving detection effects should be evaluated in large and spring, while the probability of meeting the crite- sample sizes composed of different ethnic populations. ria for MCI or dementia in winter and spring is nearly 30% higher, relative to that in the summer and autumn. Epilepsy MEF2C was found to be involved in this regulation of Due to involvement of MEF2C in many processes dur- seasonal plasticity [40]. ing neural developmental stages, functional disruption of The high expressions of MEF2C in brain regions MEF2C results in various neurological symptoms, among related to learning and memory, such as dentate gyrus, which epilepsy is a common symptom. MEF2C condi- frontal cortex, entorhinal cortex or amygdala, strongly tional knockout mice revealed that MEF2C is involved prompted the important role of MEF2C in cognition in the migration of GABA and glutamate pyramidal neu- of AD [81]. Large meta-analysis studies identified that rons, as well as in the maintenance of synaptic stability the variation of  rs190982, a common single nucleotide and function [71]. Besides, MEF2C regulates inhibitory polymorphism (SNP),  in MEF2C is a protective factor and excitatory states of neurons to maintain the balance against AD in a Caucasian population (OR = 0.93, 95% in neural networks [26]. Disruption of this regulation CI = 0.90 ~ 0.95) [66]. Besides, an association between Zhang and Zhao Molecular Brain (2022) 15:8 Page 4 of 11 Table 1 MEF2C single nucleotide polymorphisms with Alzheimer’s disease in different population Sample MEF2C Genotype Phenotype References Caucasian population SNPrs190982 Protective factor [35] Spanish population SNPrs190982 Protective factor [58] Han Chinese SNPrs190982 Eec ff t factor on cognition [42] Han Chinese SNPrs190982 No association [66] Alzheimer’s Research UK Consor- SNPrs190982 No association [8] tium DNA Bank Taiwanese SNPrs190982 No association [41] Taiwanese SNPrs9293506 TC genotype had a 2.79-fold increased risk for cognitive [41] aging compared to CC genotype Japanese MEF2C mRNA in leukocytes Positively correlated with MMSE [60] MMSE Mini-mental State Examination, SNP single nucleotide polymorphisms may lead to abnormal synaptic activities, causing epilep- in ASD patients with epilepsy, but not in ASD patients tic events. without epilepsy, indicating that MEF2C functional vari- MEF2C-related epilepsy has been reported [9, 53, 82] ation significantly increased the risk of epilepsy in ASD (Table  2). Its prevalence ranges between 54% and 82% [83]. [9, 53]. The associated genetic defects include MEF2C In recent years, molecular studies have revealed fur- pathogenic variants, or microdeletions encompassing ther pathological mechanisms involved in epilepsy. the MEF2C gene. MEF2C-related epilepsy usually occurs For instance, truncated Salt-induced kinase 1 (SIK1) during infancy or early childhood. In a review involving sequence variants p. (Glu347*) and p. (Gln633*) reduced 19 patients with MEF2C-related epilepsy, seizures were the expressions of MEF2C. The SIK1 syndrome is a established to have occurred in the first 12 months of life developmental epilepsy disorder that is caused by a hete- in 12 patients (63%). The mean age of seizure onset was rozygous mutation in the SIK1 gene (OMIM no.616341). 13.5  months (median 12), ranging from 3 to 36  months Decreased expressions of MEF2C proteins in neurons [9]. Febrile epilepsy, tonic–clonic epilepsy and myoclonic is correlated with abnormal expressions of target genes epilepsy are the most common epilepsy types. Reported (ARC, NRG1 or NR4A1), which disrupts the balance EEG abnormalities include epileptic activity, background in neuronal excitability, thereby reducing the epileptic activity disorder, and multifocal as well as generalized threshold. This process is independent of HDAC5 phos - epileptiform discharge [9]. Although the frequency of phorylation, indicating that SIK1 may directly interact early-onset epilepsy is high, some children with late with MEF2C [55]. In addition, in rat models, the expres- onset, mild seizures or no epilepsy at all exhibit serious sions of miR-203 in astrocytes were established to be neurological defects, such as low muscle tone or hyper- up-regulated, which led to down-regulation of MEF2C, activity. The severity of epilepsy is not always consistent promotion of NF- κB, phosphorylation of I κ B/IKK and with other neurological defects [49]. Certainly, patients secretion of inflammatory effectors (IL-6 and TNF-α). with complete deletion of MEF2C have an increased Besides, LncRNAUCA1 (long-chain non-coding RNA risk for developing epilepsy, relative to those with partial urothelial carcinoma associated 1) inhibits inflamma - deletion [57]. tory responses to epilepsy by modulating miR203-medi- Etiopathogenic factors in other conditions are also ated regulation of the MEF2C/NF-κB signaling pathway, associated with MEF2C in epilepsy. Among 73 patients therefore, it may be a potential therapeutic target for epi- with infantile spasm syndrome (ISS), an age-related epi- lepsy [80]. leptic syndrome, one patient with 3.24  Mb deletion in 5q14.3 located in 1  Mb upstream of the MEF2C gene Nervous system tumor was found [arr5q14.3q15 (890, 687, 77 ~ 923, 160, 85) x1, The activities of MEF-2 are regulated by various factors, hg19] [10]. Bienvenu et  al. identified a case of de novo including alternative splicing, post-translational modifi - MEF2C mutation in 50 patients with unexplained epi- cation of C-terminal and dimerization of N-terminal with leptic encephalopathy [7]. Moreover, Yu et  al. and Zhou other transcription factors [44]. Not only are mutations et al. reported cases of infantile spasm caused by a 5q14.3 in these regions associated with developmental abnor- microdeletion syndrome in China [79, 82]. Another study malities, they are also associated with tumors, leukemia documented a 9.68% rare functional variation of MEF2C and transcriptional abnormalities. MEF2C diversifies Zhang and Zhao Molecular Brain (2022) 15:8 Page 5 of 11 Table 2 Genomic data and key features of epilepsy for 42 patients with MEF2C-relative epilepsy Genetic defect Epilepsy phenotype References 1 De novo, likely pathogenic heterozygous variant, MEF2C: c.236 G > C Focal impaired awareness motor seizures [9] (p.Arg79Pro) 2 De novo, missense variant, MEF2C: c.48C > G (p.Asn16Lys) Focal seizures [75] 3 Pathogenic heterozygous variant, MEF2C: c.565C > T (p.Arg189) Not reported [75] 4 Heterozygous variant, MEF2C: c.334 G > T (p.Glu112) Focal seizures [75] 5 De novo, heterozygous variant, MEF2C: c.403-1 G > T Febrile seizures, followed by afebrile seizures [75] 6 De novo, pathogenic heterozygous variant, MEF2C: c.766C > T (p.Arg256) Febrile seizures [75] 7 5q14.3q15 del, GC Chr5: 88 098 253-88 592 348 Febrile seizures [73] 8 5q14.3q15 del, GC Chr5: 88 034 622-88 164 453 Febrile seizures, followed by generalized seizures [73] 9 5q14.3q15 del, GC Chr5: 88 193 289-88 450 318 Febrile seizures, followed by generalized and absence seizures [73] 10 De novo, pathogenic heterozygous variant, MEF2C: c.220 G > T Febrile seizures and afebrile seizures [73] (p.Glu74Ter, premature stop codon) 11 MEF2C deletion, exons1–2 (MLPA) Not reported [73] 12 De novo, pathogenic missense heterozygous variant, MEF2C: c.9A > T Atypical absence, atonic, myoclonic and refractory seizures [57] (p.R3S) 13 5q14.3 del (0.01 Mb), GC Chr5: 88 110 707–88 278 367 Not reported [68] 14 De novo, missense heterozygous variant, MEF2C: c.258 G > A (p.E86E) Not reported [65] 15 Pathogenic frameshift variant, MEF2C: c.833delT (p.Leu278Terfs) Myoclonic and atonic seizures [53] 16 5q14.3 del (0.05 Mb), GC Chr5: 880 519 70-881 045 35 Not reported [53] 17 Pathogenic frameshift heterozygous variant, MEF2C c.457delA Myoclonic and febrile seizures [7] (p.Asn153ThrfsX33) 18 5q14.3 del (3.6 Mb), GC Chr5: 85,855,118–89,474,751 ISS [53] 19 5q14.3 del (5.11 Mb), GC Chr5: 85,684,257–90,798,560 Myoclonic epilepsy [53] 20 5q14.3 del (1.0 Mb), GC Chr5: 88,018,766–89,063,989 Not reported [53] 21 5q14.3 del (1.38 Mb), GC Chr5: 87,905,325–89,289,023 Myoclonic epilepsy, followed by ISS [53] 22 5q14.3 del (0.32 Mb), GC Chr5: 87,905,325–88,220,403 Myoclonic and generalized epilepsy [53] 23 Frameshift Mutation in MEF2C, c833delT Myoclonic and atonic epilepsy [53] 24 5q14.3 del (1.95 Mb), GC Chr5: 87,566,009–89,505,509 Myoclonic epilepsy and ISS [53] 25 5q14.3 del (6.0 Mb), GC Chr5: 87,719,139–93,736,389 ISS [53] 26 5q14.3 del (11.6 Mb), GC Chr5: 81,657,245–93,240,731 Febrile seizures [53] 27 5q14.3 del (5.4 Mb), GC Chr5: 88,185,348–93,546,896 Myoclonic epilepsy [53] 28 5q14.3 del (0.41 Mb), GC Chr5: 88,177,038–88,592,311 Febrile seizures [53] 29 5q14.3 del (5.2 Mb), GC Chr5: 84,520,000–89,800,000 Myoclonic epilepsy [53] 30 De novo, pathogenic missense heterozygous variant, MEF2C: c.113T > A Not reported [86] (p.Leu38Gln) 31 De novo, heterozygous 1-bp duplication of the MEF2C gene: 99dupT Complex partial seizure [86] (p.E34X) 32 Pathogenic variant, MEF2C: c.226_236del11 (p.H76fsX15) Not reported [86] 33 De novo, heterozygous missense variant, MEF2C:c.80 G > C (p.Gly27Ala) Not reported [86] 34 De novo, heterozygous nonsense variant, 683C-G transversion in exon 7 Not reported [36] of the MEF2C gene 35 5q14 del (0.02 Mb), GC Chr5: 87 770 283-88 051 970 Febrile seizures [36] 36 5q14.3 del (3.24 Mb), arr5q14.3q15 (890 687 77-923 160 85) × 1, hg19 ISS [10] 37 5q14.3 del (5.69 Mb), arr cgh 5q14.3q15 (rs10514301 − rs9314105) × 1 ISS, occasional seizures [22] dn 38 5q14.3 del (3.6 Mb), arr cgh 5q14.3 (RP11-291O24-RP11-62E10) × 1 dn Febrile seizure [22] 39 5q14.3-q15 del (3.574 Mb), arr cgh 5q14.3q15 Atypical absences, followed by complex partial seizures [22] (rs10223241 − rs17664587) × 1 dn 40 5q14.3-q21.3 del (17 Mb), GC Chr5:88 945 075–105 929 555 Febrile seizures, followed by generalized tonic–clonic seizures [14] 41 5q14.3-q15 del (8.4 Mb), GC Chr5: 87 086 298–95 538 699 ISS, epileptic spasms [14] 42 5q14.3-q15 del (6.3 Mb), GC Chr5: 88 659 488–94 986 600 Episodes of unresponsiveness, followed by myoclonic seizures [14] Del deletion, GC genomic coordinates, Mb megabase, ISS infantile spasms Zhang and Zhao Molecular Brain (2022) 15:8 Page 6 of 11 hematological tumors, pancreatic cancer or liver cancer, behaviors. Although there are many etiological mod- leading to exhibition of various tumor characteristics els for ASD, such as gene mutations, abnormal synaptic [17]. MEF2C plays an important role in tumor patho- development or signaling pathways, its pathogenesis has genesis and development, however, a limited number of not been conclusively determined. One of the mecha- studies have evaluated its functions in nervous system nisms involved in ASD pathogenesis is the imbalance tumors [21, 78]. in excitatory/inhibitory synaptic ratio [15]. Synaptic A study on brain metastases of breast cancer  (BCBM) formation dominates the early stages of brain develop- demonstrated that MEF2C, as a target gene of miR- ment, resulting in the generation of more synapses than 802-5p and miR-194-5p, is increased in metastatic tumor are needed for brain functions. Consequently, the cells. Immunoreactivity analyses showed that MEF2C brain prunes the extra synapses [27]. MEF2C plays an expression increased by 24% between the 3rd and 10th important role in activity-dependent synaptic elimina- day of brain metastasis (p < 0.001), and by 20% between tion. When depolarization and calcium influx occur in the 7th and 10th day (p < 0.001). Therefore, as a tran - neurons after stimulation, MEF2C is activated, then it scription factor, MEF2C promotes the development of induces the transcription of protocadherin-10 (Pcdh10). metastatic tumors. It was also found that peritumoral Pcdh10 mediates the degradation of synaptic scaffold astrocytes began to express MEF2C after exudation of protein 95 (PSD-95) by binding ubiquitin PSD-95 to the tumor cells from tumor tissues, while non-peritumoral proteasome, leading to elimination of excitatory synapses astrocytes did not show these expressions, suggesting [64, 69]. that MEF2C is involved in the crosstalk between astro- Dysfunctions of the MEF2C gene may prevent the cytes and tumor cells during the development of BCBM  brain from eliminating unwanted excitatory synapses, [61]. leading to ASD-like syndromes (Table  3). A previous In the cytoplasm, MEF2C was shown to impair study reported a significant increase in the number of β-catenin translocation into the nucleus, thereby inhib- excitatory synapses and spinous processes in MEF2C-KO iting Wnt/β-catenin signaling during the early stages of mice, as well as enhancement of basal and evoked synap- metastases development. However, in advanced stages, tic transmission. This cascade of events led to develop - MEF2C and Wnt/β-catenin translocated to the nucleus, ment of hippocampal dependent learning and memory which was accompanied by an increase in Ki-67 positive impairments, as well as ASD-like social behavior defects cells. Continuous expression of MEF2C and its translo- [6]. Conditional MEF2C KO in neural stem/progenitor cation to the nucleus is associated with disease severity, cells expressing Nestin can affect neuronal differentia - and MEF2C may serve as a biomarker for BCBM devel- tion, resulting in abnormal density and cell body sizes of opment and prognosis as well as its potential therapeutic cortical plate neurons, without affecting the proliferation target [24]. as well as survival of neural stem cells. The conditioned The dual role of MEF2C in tumors has also been MEF2C-KO mice that survived to adulthood showed reported in liver cancer. In the nucleus of hepatocellular more immature electrophysiological network charac- carcinoma, MEF2C promoted the invasion and angiogen- teristics and serious behavioral defects, indicating that esis of hepatocellular carcinoma cells, while cytoplasmic MEF2C plays a key role in early programming of neu- MEF2C isolated β-catenin in the cytoplasm and reduced ronal differentiation and distribution of neocortical layers the ability of β-catenin to promote cell proliferation. Sub- in ASD [5]. Unlike the previous thought that MEF2C was cellular distribution of MEF2C may determine the over- only expressed in the cerebral cortex and hippocampus all role of MEF2C [5]. On the other hand, after being [2], recent studies have found that MEF2C was  specifi - assembled into multi-protein complexes as transcrip- cally expressed in the Purkinje cell layer of the cerebrum tion factors, MEF2C can be transformed into transcrip- [32]. It selectively regulates the development of dendrites tion activators or inhibitors under the control of tumor of Purkinje cells and prunes the synapses of climbing fib - microenvironments to produce the opposite effects [44]. ers. Similar with ASD findings, deletion or downregula - Therefore, MEF2C may act as a “double-edged sword” tion of MEF2C resulted in increased dendritic branches (either as a proto-oncogene or a tumor suppressor) in and spines in Purkinje cells, and changes in excitatory as tumor pathogenesis. well as inhibitory synaptic protein localization [37, 39]. Essentially, the increased spines are immature spines that Autism spectrum disorders are most likely to be pruned later, resulting in a decrease Autism spectrum disorders (ASD) are a group of severe in the number of neurons and a decline in overall func- neurodevelopmental disorders that are characterized by tions [45]. impaired social interactions and communication skills, Studies on deletions of MEF2C in frontal brain regions and/or narrow interests and repetitive stereotyped of conditioned MEF2C-KO mice after birth, using Zhang and Zhao Molecular Brain (2022) 15:8 Page 7 of 11 Table 3 Neural phenotype and behavior phenotype in manipulation of MEF2C Sample Neural phenotype Behavior phenotype References Calcium/calmodulin-dependent protein kinase II (CaMKII)- Increased the number of spines in the hippocampus of mice Not related with the presentation of learning and memory, [16] Cre93 line conditioned MEF2C-KO mice after birth LTP or social behavior Late embryonic deletion of MEF2C in the forebrain Increased the number of excitatory synapses and spinous Hippocampus-dependent learning and memory impair- [6] Transgenic expression of a superactive form of MEF2C in processes ment neurons Enhanced basal and evoked synaptic transmission of mice (NSE-MEF2C-VP16 transgenic mice) Reduced structural and functional glutamatergic synapse density in hippocampal pyramidal neurons Conventional exon 2-deleted allele of MEF2 deletion or Increased dendritic branches and spines in Purkinje cells, [37, 39] downregulation of MEF2C and changes in excitatory and inhibitory synaptic protein localization Conditional MEF2C gene KO in neural stem/progenitor cell Abnormal density and cell body size of cortical plate More immature electrophysiological network characteristics [5] neurons and serious behavioral defects Knockdown of MEF2C Reduced the number of dendritic spines on apical dendrites Hyper-sensitive passive avoidance behavior [31] Overexpression of MEF2C of cultured neural progenitor cells Increased spine density Embryonic MEF2C deletion from most forebrain excitatory A ~ twofold increase in dendritic GABAergic synapse density Deficits in fear learning and memory, multiple social [26] neurons in mice (EmxCre × MEF2C flox/flox) on excitatory cortical pyramidal neurons behaviors, socially-motivated ultrasonic vocalizations, and reward-related behaviors HSV-Cre-GFP virus injection in MEF2C flox/flox pups at P2 to Increased in spine counts in SPNs at P8 Defective neonatal isolation-induced USVs, a form of vocal [18] down-regulate MEF2C expression Normal number of dendritic spines in SPNs at P19-20 communication in neonatal rodents HSV-Cre-GFP virus injection in MEF2C flox/flox mice at P14- Decreased number of spines in SPNs at P14 15 to down-regulate MEF2C expression In utero electroporation of pcBIG-Mef2C-VP16 plasmids at E12.5 in wild-type embryos to overexpress MEF 2C Postnatal MEF2C deletion Decreased excitatory synapse number from L4 / L2/3 [56] AAV-Cre-GFP infection in dissociated neocortical cultures pyramidal neurons A reduced spine density on basal of normal dendritic branching in neurons Conventional exon 2-deleted allele of MEF2C Reduced number of neurons and total dendritic lengths Intellectual disability, speech deficit, autism-like symptoms, [70] Dendritic interactions impairment seizures or motor abnormalities Increased E/I ratio in the hippocampus Upregulation of MEF2C in the adult prefrontal cortex (PFC) Decrease in mushroom spines proportion in layer III of the Improved cognition [47] by AAV-MEF2C virus injections PFC with no difference in total spine density SPNs striatal projecting neurons Zhang and Zhao Molecular Brain (2022) 15:8 Page 8 of 11 the calcium/calmodulin-dependent protein kinase II prefrontal lobe are highly associated with disability. In (CaMKII)-Cre93 line, showed that although the number a study involving 150,000 participants, the Psychiatric of spines in the hippocampus of mice increased signifi - Genome Association identified 108 different genome loci cantly, these increases were not related with presentation associated with schizophrenia [51]. There are MEF2C of learning and memory, long-term potentiation (LTP) target sites in the heritable risk factors for schizophrenia, or social behaviors [16]. In spite of continuous roles of which associate MEF2C with this disease. MEF2C in negative regulation of synaptogenesis, the An enrichment of MEF2C motifs in the SNP pool, with functions of MEF2C, which involves the regulation of the top score being related to schizophrenia was reported synaptic plasticity, learning and memory or behavio- [47]. Sequencing data of chromatin-associated histone ral expressions in ASD may depend on expressions of methylation in the prefrontal neuronal chromatin of 17 MEF2C during embryonic development, rather than just schizophrenic patients showed that MEF2C-binding regulation of the number of synapses [1]. motifs were significantly overexpressed in about 1000 There is a significant overlap between the genes regu - nucleosome sequences, affected by histone H3K4 hyper - lated by MEF2C and dozens of candidate ASD risk genes methylation. The hypermethylated sequence of trime - [26]. For instance, ASD-related symptoms have been thyl-histone H3-lysine 4 (H3K4me3) exhibited a strong reported in some patients with MEF2C haploid insuf- neuronal footprint, with 6/12 of Gene Ontological (GO) ficiency syndrome (MCHS) [72]. MCHS, a neurodevel - categories being associated with synapses and neurons, opmental disorder, is caused by microdeletion, missense and 8/18 of “drug” and “phenotypic” categories being or nonsense mutations in the MEF2C gene or copy num- matched with decreased cognition and abnormal behav- ber variations (CNVs). Chromosomal microarray data iors. Down-regulation of MEF2C in cell culture models revealed that MEF2C mutations are scattered throughout showed hypermethylation of H3K4 in affected nucle - the MEF2C protein, without thermal mutation regions. osomes, similar to the changes observed in prefrontal The patients showed varying degrees of intellectual dis - lobes of schizophrenia. Increasing expressions of MEF2C abilities, speech deficits, autism-like symptoms, seizures in the prefrontal lobe of cognitive impaired mice models or motor abnormalities [36]. In general, phenotypic char- with schizophrenia by using adeno-associated virus vec- acteristics of MCHS may present dysplasia of multiple tors significantly improved cognitive abilities. Following nerve cell populations at the transcriptional level, with treatment with the NMDA receptor antagonist, MK-801, ASD syndromes being the most pronounced [57]. the cognitive performance of mice with up-regulated Rett syndrome, one of the serious neurodevelopmen- MEF2C levels were better compared to those of normal tal diseases, which occurs mostly in women. It is char- mice. Therefore, MEF2C transcription factors are prom - acterized by progressive decline in motor skills and ising targets for treatment of schizophrenia-associated intelligence. The MeCP2 mutation allele in region q28 on cognitive impairment [30]. X chromosome has been shown to trigger the Rett syn- drome [38]. Jiaping W et  al. found 3 MEF2C heterozy- gous mutations in 44 patients with the Rett syndrome, Summary without MeCP2 gene mutations, suggesting the MEF2C MEF2C plays a significant role in early brain develop - gene mutation is one of the risk factors for Rett syndrome ment of humans or animals, and in normal develop- [74]. Based on definitive pathogenesis of MeCP2 gene ment, distribution and electrical activity of neocortical mutations, DSM-5 removed Rett syndrome from the neurons. Besides, it has a profound effect on neuropsy - diagnosis of ASD in 2013. However, this change has been chiatric phenotypes. Because of the important effects of questioned by many scholars. Since ASD is diagnosed MEF2C on synapses, MEF2C gene mutations or dysfunc- via language as well as behavioral symptoms and is also tions will lead to a series of syndromes, including intel- caused by genetic variations, it may not remove a subtype lectual deficiency, epilepsy and autism-like symptoms. of ASD when one pathogenic gene is found. According to The association between MEF2C and cognitive impair - current studies, some of the patients diagnosed with Rett ment coincides with the role of MEF2C in AD and ASD. syndromes do not have the MeCP2 gene mutation, but In view of similar symptoms caused by MEF2C defects share common pathogenic genes with ASD. Therefore, in various neuropsychiatric disorders, we recommend more evidence is needed to distinguish Rett syndrome that it be described as MEF2C-related syndrome, which from ASD. would be contribute to identify characteristic gene- related symptoms from these complex neuropsychiatric disorders. 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Progress on the roles of MEF2C in neuropsychiatric diseases

Molecular Brain , Volume 15 (1) – Jan 6, 2022

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Abstract

Myocyte Enhancer Factor 2 C (MEF2C), one of the transcription factors of the MADS-BOX family, is involved in embry- onic brain development, neuronal formation and differentiation, as well as in the growth and pruning of axons and dendrites. MEF2C is also involved in the development of various neuropsychiatric disorders, such as autism spectrum disorders (ASD), epilepsy, schizophrenia and Alzheimer’s disease (AD). Here, we review the relationship between MEF2C and neuropsychiatric disorders, and provide further insights into the mechanism of these diseases. Keywords: MEF2C, Transcription factor, Synapse, Neurodevelopment, Neuropsychiatric disease well as recruitment of cofactors. TAD is involved in the Introduction recruitment of cofactors, including co-activators such MEF2C is an important member of the myocyte enhancer as histone acetyltransferase p300 and cAMP-response factor 2 (MEF2). MEF2 is a subfamily of the MADS-BOX element-binding protein-binding protein (CBP), or co- (MCM-1-agamous-deficiens-serum response factor) repressors such as class II histone deacetylases (HDACs), family of transcriptional regulatory factors, which play that regulates transcription [4]. Besides, through alter- essential roles in embryogenesis and epigenetic modifica - native splicing at the mRNA level [85], and post-trans- tions that control gene expressions during development lational modifications such as phosphorylation or and throughout adulthood [23]. The MEF2 family consist dephosphorylation [11], acetylation [3], sumoylation [63] of four members MEF2A, MEF2B, MEF2C and MEF2D. and S-nitrosylation [52], MEF2C appears various expres- MEF2C is the earliest expressed MEF2 isomer in the tel- sion pattern and transactivation functions. In addition, encephalon of mouse embryos, and is the most expressed MEF2C mediates physiological processes such as cardiac in the cerebral cortex of postnatal and adult mouse morphogenesis, angiogenesis, muscle cell differentia - brains. Therefore, it is critical for proper nervous system tion, bone development, and neural or lymphatic system development and functional maintenance [4]. development [44]. The human MEF2C gene is located in  the  chromo - In the absence of external stimulation, the MEF2 pro- some 5q14.3  region and its protein consists of five core tein in the central nervous system binds and inactivates domains; MADS domain, MEF2 domain, transcriptional target genes. Various stimuli, such as depolarization, activation domains 1 (TAD1) and 2 (TAD2), as well as the neurotrophin or synaptic stimulation (e.g., glutamate nuclear localization signal (NLS). The MADS and MEF2 synaptic Reelin) activates neurons, thereby triggering cal- domains mediate MEF2C dimerization, DNA binding as cium signaling responses, including calmodulin-depend- ent protein kinase (CaMK), leading to phosphorylation *Correspondence: yongxiang_Zhao@126.com of class IIa HDACs. These phosphorylation events cause National Center for International Research of Bio-Targeting Theranostics, to a nuclear output of HDACs, and their subsequent Guangxi Key Laboratory of Bio-Targeting Theranostics, Collaborative removal from the MEF2 target gene, allowing the recruit- Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Medical University, Nanning 530021, Guangxi, China ment of co-activators [46]. MiR-124 and miR-9 have been Full list of author information is available at the end of the article shown to co-inhibit HDACs 5 expressions, which activate © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Zhang and Zhao Molecular Brain (2022) 15:8 Page 2 of 11 the neuron membrane glycoprotein, GPM6A, a MEF2C Alzheimer’s disease target gene. These activities promote the development of AD is a neurodegenerative disease that is associated axons in primary neurons (Fig. 1) [25]. with progressive cognitive and memory deterioration. In addition, protein phosphatase 2B or calcineurin Inflammation is involved in AD pathogenesis [19]. As can directly dephosphorylate MEF2, thereby affecting the first and main immune defense component of central its affinity towards target DNA sequences, and promot - nervous system (CNS), microglia act as macrophages, ing its transcription activities [43]. MEF2C is involved clearing metabolites and necrotic cells in the brain in regulation of neuronal migration, activity-dependent through phagocytosis. However, continuous activation cell survival, neuronal differentiation, axon guidance and of microglia leads to the secretion of various neurotoxic pruning, dendritic formation and remodeling, as well as substances, which play an important role in AD devel- in synaptic development and neuronal excitability [37, opment [54]. For instance, when interferon-β (IFN-β), a 39, 84]. In the last decade, human genome-wide asso- pro-inflammatory cytokine related to brain ageing, was ciation study (GWAS) and genome sequencing of large injected into the cerebrospinal fluid of young wild type patient samples revealed that MEF2C is a candidate risk (WT) or MEF2C-knock out (MEF2C-KO) mice, sup- gene for various neuropsychiatric disorders, such as AD pressed social interaction outcomes were observed in [67], ASD [83], schizophrenia [47], bipolar disorder [50], the MEF2C-KO mice, compared to WT mice. Following major depression [28], attention deficit and hyperactiv - immune activations, the expressions of pro-inflammatory ity disorder [62], epilepsy [80] or Parkinson’s disease [59]. chemokines (CCL2 and CCL5) and cytokines (IL-1b We review recent findings on MEF2C as well as its role in and TNF) in MEF2C-KO mice were significantly higher some neuropsychiatric diseases and provide theoretical than in WT mice. uTh s MEF2C enhances the resil - and detailed insights that will inform future studies. ience of microglia to immune challenges and promotes Fig. 1 The functional regulation model of MEF2C in neuronal cells, where MEF2C is particularly important for the regulation of dendritic spines. The blue italics are MEF2C-associated psychoneurotic disorders Zhang and Zhao Molecular Brain (2022) 15:8 Page 3 of 11 homeostasis in pre-inflammatory states. Type I inter - rs190982 polymorphism and AD (OR = 0.885, 95% feron (IFN-I) accumulation down-regulates the MEF2C CI = 0.811 ~ 0.966) has been reported [10]. Based on in microglia, leading to excess microglia responses analyses of pathological data on AD, among 22 genetic under pro-inflammatory environments of AD or aging variations of AD, the rs190982 variation in MEF2C brains, and aggravates cognitive impairment and disease gene, was the only one that was found to exert signifi - pathology [20]. As reported by Xue et al., the suppressed cant effects on cognitive functions [42]. However, other MEF2C nuclear translocation as an early and prominent studies have reported the negative association [8, 66]. A microglial phenotype in a mouse model of brain amy- genome-wide association studies (GWAS) meta-analysis loidosis (5 × FAD mice) implies an association between involving a Taiwanese population of China did not reveal MEF2C deregulation and microglial phenotypes in AD- positive association between MEF2Crs190982 polymor- relative settings. Although they did not report the down- phism and AD, however, there were interactions between regulation of MEF2C mRNA copies in the microglia of MEF2Crs9293506 and cognitive aging. The risk for cog - 5 × FAD mice, upregulated MEF2C in microglia after nitive aging in carriers with TC genotypes of MEF2C anti-IFNAR antibody administration implies a potential rs9293506 was 2.79 times higher than that of those with strategy for improving microglial elasticity by upregu- the CC genotype [41]. These variations may be attributed lation of MEF2C [77]. A significant decrease in MEF2C to genetic heterogeneities among different ethnic groups, mRNA levels in leukocytes of AD patients has been such as differences in minor alleles, different frequencies positively correlated with total scores of Mini-Mental of secondary alleles or heterogeneity of potential genetic State Examination (MMSE). Therefore, expression levels structures. of MEF2C mRNA in leukocytes may not only be a bio- In a 2013 meta-analysis, Lambert et  al. found a marker for AD diagnosis, but be a potential biomarker genome-wide significant association between MEF2C for early detection of cognitive decline, such as mild cog- and AD [35], however, the significant association was nitive impairment (MCI) [60]. not replicated in a larger sample study performed in 2019 In addition, MEF2C plays an important role in amy- [34]. Moreover, Jansen et  al. were unable to establish an loid-protein precursor protein (APP) -mediated anti- association between MEF2C and AD in a large sample apoptotic neuroprotection [12]. MEF2C is a potential study from the UK Biobank (UKB) [29]. regulator of APP proteolysis, during which amyloid beta Although GWAS have been a valuable platform for (Aβ), a central factor in AD initiation, is produced [13]. identifying candidates for disease-related genetic vari- These findings elucidate on pathways involved in oligo - ants, the confirmed risk loci for AD only explains a small meric Aβ-potentiated microglial activation. portion of AD heritability (Table  1). To address some of Methyl CpG binding protein 2 (MeCP2; an impor- the limitations encountered by univariate SNP-based tant transcriptional inhibitor) levels have been shown to analyses, advanced methods were  developed to examine be increased in the cerebral cortex and hippocampus of SNPs in aggregate. The aggregated SNP approach may AD patients. MeCP2-mediated MEF2C inhibition may reduce the total number of tests performed and increase be associated with cognitive decline in AD [33]. Inter- power by exploiting linkage disequilibrium (LD) across estingly, other studies have reported a significant corre - multiple SNPS [76]. It hypothesized that variations in lation between cognitive functions and seasons among entire gene regions, rather than isolated single SNPS, the elderly. There is a 4-year difference in cognitive func - play a role in cognitive decline [48]. Other strategies for tions between summer and autumn, compared to winter improving detection effects should be evaluated in large and spring, while the probability of meeting the crite- sample sizes composed of different ethnic populations. ria for MCI or dementia in winter and spring is nearly 30% higher, relative to that in the summer and autumn. Epilepsy MEF2C was found to be involved in this regulation of Due to involvement of MEF2C in many processes dur- seasonal plasticity [40]. ing neural developmental stages, functional disruption of The high expressions of MEF2C in brain regions MEF2C results in various neurological symptoms, among related to learning and memory, such as dentate gyrus, which epilepsy is a common symptom. MEF2C condi- frontal cortex, entorhinal cortex or amygdala, strongly tional knockout mice revealed that MEF2C is involved prompted the important role of MEF2C in cognition in the migration of GABA and glutamate pyramidal neu- of AD [81]. Large meta-analysis studies identified that rons, as well as in the maintenance of synaptic stability the variation of  rs190982, a common single nucleotide and function [71]. Besides, MEF2C regulates inhibitory polymorphism (SNP),  in MEF2C is a protective factor and excitatory states of neurons to maintain the balance against AD in a Caucasian population (OR = 0.93, 95% in neural networks [26]. Disruption of this regulation CI = 0.90 ~ 0.95) [66]. Besides, an association between Zhang and Zhao Molecular Brain (2022) 15:8 Page 4 of 11 Table 1 MEF2C single nucleotide polymorphisms with Alzheimer’s disease in different population Sample MEF2C Genotype Phenotype References Caucasian population SNPrs190982 Protective factor [35] Spanish population SNPrs190982 Protective factor [58] Han Chinese SNPrs190982 Eec ff t factor on cognition [42] Han Chinese SNPrs190982 No association [66] Alzheimer’s Research UK Consor- SNPrs190982 No association [8] tium DNA Bank Taiwanese SNPrs190982 No association [41] Taiwanese SNPrs9293506 TC genotype had a 2.79-fold increased risk for cognitive [41] aging compared to CC genotype Japanese MEF2C mRNA in leukocytes Positively correlated with MMSE [60] MMSE Mini-mental State Examination, SNP single nucleotide polymorphisms may lead to abnormal synaptic activities, causing epilep- in ASD patients with epilepsy, but not in ASD patients tic events. without epilepsy, indicating that MEF2C functional vari- MEF2C-related epilepsy has been reported [9, 53, 82] ation significantly increased the risk of epilepsy in ASD (Table  2). Its prevalence ranges between 54% and 82% [83]. [9, 53]. The associated genetic defects include MEF2C In recent years, molecular studies have revealed fur- pathogenic variants, or microdeletions encompassing ther pathological mechanisms involved in epilepsy. the MEF2C gene. MEF2C-related epilepsy usually occurs For instance, truncated Salt-induced kinase 1 (SIK1) during infancy or early childhood. In a review involving sequence variants p. (Glu347*) and p. (Gln633*) reduced 19 patients with MEF2C-related epilepsy, seizures were the expressions of MEF2C. The SIK1 syndrome is a established to have occurred in the first 12 months of life developmental epilepsy disorder that is caused by a hete- in 12 patients (63%). The mean age of seizure onset was rozygous mutation in the SIK1 gene (OMIM no.616341). 13.5  months (median 12), ranging from 3 to 36  months Decreased expressions of MEF2C proteins in neurons [9]. Febrile epilepsy, tonic–clonic epilepsy and myoclonic is correlated with abnormal expressions of target genes epilepsy are the most common epilepsy types. Reported (ARC, NRG1 or NR4A1), which disrupts the balance EEG abnormalities include epileptic activity, background in neuronal excitability, thereby reducing the epileptic activity disorder, and multifocal as well as generalized threshold. This process is independent of HDAC5 phos - epileptiform discharge [9]. Although the frequency of phorylation, indicating that SIK1 may directly interact early-onset epilepsy is high, some children with late with MEF2C [55]. In addition, in rat models, the expres- onset, mild seizures or no epilepsy at all exhibit serious sions of miR-203 in astrocytes were established to be neurological defects, such as low muscle tone or hyper- up-regulated, which led to down-regulation of MEF2C, activity. The severity of epilepsy is not always consistent promotion of NF- κB, phosphorylation of I κ B/IKK and with other neurological defects [49]. Certainly, patients secretion of inflammatory effectors (IL-6 and TNF-α). with complete deletion of MEF2C have an increased Besides, LncRNAUCA1 (long-chain non-coding RNA risk for developing epilepsy, relative to those with partial urothelial carcinoma associated 1) inhibits inflamma - deletion [57]. tory responses to epilepsy by modulating miR203-medi- Etiopathogenic factors in other conditions are also ated regulation of the MEF2C/NF-κB signaling pathway, associated with MEF2C in epilepsy. Among 73 patients therefore, it may be a potential therapeutic target for epi- with infantile spasm syndrome (ISS), an age-related epi- lepsy [80]. leptic syndrome, one patient with 3.24  Mb deletion in 5q14.3 located in 1  Mb upstream of the MEF2C gene Nervous system tumor was found [arr5q14.3q15 (890, 687, 77 ~ 923, 160, 85) x1, The activities of MEF-2 are regulated by various factors, hg19] [10]. Bienvenu et  al. identified a case of de novo including alternative splicing, post-translational modifi - MEF2C mutation in 50 patients with unexplained epi- cation of C-terminal and dimerization of N-terminal with leptic encephalopathy [7]. Moreover, Yu et  al. and Zhou other transcription factors [44]. Not only are mutations et al. reported cases of infantile spasm caused by a 5q14.3 in these regions associated with developmental abnor- microdeletion syndrome in China [79, 82]. Another study malities, they are also associated with tumors, leukemia documented a 9.68% rare functional variation of MEF2C and transcriptional abnormalities. MEF2C diversifies Zhang and Zhao Molecular Brain (2022) 15:8 Page 5 of 11 Table 2 Genomic data and key features of epilepsy for 42 patients with MEF2C-relative epilepsy Genetic defect Epilepsy phenotype References 1 De novo, likely pathogenic heterozygous variant, MEF2C: c.236 G > C Focal impaired awareness motor seizures [9] (p.Arg79Pro) 2 De novo, missense variant, MEF2C: c.48C > G (p.Asn16Lys) Focal seizures [75] 3 Pathogenic heterozygous variant, MEF2C: c.565C > T (p.Arg189) Not reported [75] 4 Heterozygous variant, MEF2C: c.334 G > T (p.Glu112) Focal seizures [75] 5 De novo, heterozygous variant, MEF2C: c.403-1 G > T Febrile seizures, followed by afebrile seizures [75] 6 De novo, pathogenic heterozygous variant, MEF2C: c.766C > T (p.Arg256) Febrile seizures [75] 7 5q14.3q15 del, GC Chr5: 88 098 253-88 592 348 Febrile seizures [73] 8 5q14.3q15 del, GC Chr5: 88 034 622-88 164 453 Febrile seizures, followed by generalized seizures [73] 9 5q14.3q15 del, GC Chr5: 88 193 289-88 450 318 Febrile seizures, followed by generalized and absence seizures [73] 10 De novo, pathogenic heterozygous variant, MEF2C: c.220 G > T Febrile seizures and afebrile seizures [73] (p.Glu74Ter, premature stop codon) 11 MEF2C deletion, exons1–2 (MLPA) Not reported [73] 12 De novo, pathogenic missense heterozygous variant, MEF2C: c.9A > T Atypical absence, atonic, myoclonic and refractory seizures [57] (p.R3S) 13 5q14.3 del (0.01 Mb), GC Chr5: 88 110 707–88 278 367 Not reported [68] 14 De novo, missense heterozygous variant, MEF2C: c.258 G > A (p.E86E) Not reported [65] 15 Pathogenic frameshift variant, MEF2C: c.833delT (p.Leu278Terfs) Myoclonic and atonic seizures [53] 16 5q14.3 del (0.05 Mb), GC Chr5: 880 519 70-881 045 35 Not reported [53] 17 Pathogenic frameshift heterozygous variant, MEF2C c.457delA Myoclonic and febrile seizures [7] (p.Asn153ThrfsX33) 18 5q14.3 del (3.6 Mb), GC Chr5: 85,855,118–89,474,751 ISS [53] 19 5q14.3 del (5.11 Mb), GC Chr5: 85,684,257–90,798,560 Myoclonic epilepsy [53] 20 5q14.3 del (1.0 Mb), GC Chr5: 88,018,766–89,063,989 Not reported [53] 21 5q14.3 del (1.38 Mb), GC Chr5: 87,905,325–89,289,023 Myoclonic epilepsy, followed by ISS [53] 22 5q14.3 del (0.32 Mb), GC Chr5: 87,905,325–88,220,403 Myoclonic and generalized epilepsy [53] 23 Frameshift Mutation in MEF2C, c833delT Myoclonic and atonic epilepsy [53] 24 5q14.3 del (1.95 Mb), GC Chr5: 87,566,009–89,505,509 Myoclonic epilepsy and ISS [53] 25 5q14.3 del (6.0 Mb), GC Chr5: 87,719,139–93,736,389 ISS [53] 26 5q14.3 del (11.6 Mb), GC Chr5: 81,657,245–93,240,731 Febrile seizures [53] 27 5q14.3 del (5.4 Mb), GC Chr5: 88,185,348–93,546,896 Myoclonic epilepsy [53] 28 5q14.3 del (0.41 Mb), GC Chr5: 88,177,038–88,592,311 Febrile seizures [53] 29 5q14.3 del (5.2 Mb), GC Chr5: 84,520,000–89,800,000 Myoclonic epilepsy [53] 30 De novo, pathogenic missense heterozygous variant, MEF2C: c.113T > A Not reported [86] (p.Leu38Gln) 31 De novo, heterozygous 1-bp duplication of the MEF2C gene: 99dupT Complex partial seizure [86] (p.E34X) 32 Pathogenic variant, MEF2C: c.226_236del11 (p.H76fsX15) Not reported [86] 33 De novo, heterozygous missense variant, MEF2C:c.80 G > C (p.Gly27Ala) Not reported [86] 34 De novo, heterozygous nonsense variant, 683C-G transversion in exon 7 Not reported [36] of the MEF2C gene 35 5q14 del (0.02 Mb), GC Chr5: 87 770 283-88 051 970 Febrile seizures [36] 36 5q14.3 del (3.24 Mb), arr5q14.3q15 (890 687 77-923 160 85) × 1, hg19 ISS [10] 37 5q14.3 del (5.69 Mb), arr cgh 5q14.3q15 (rs10514301 − rs9314105) × 1 ISS, occasional seizures [22] dn 38 5q14.3 del (3.6 Mb), arr cgh 5q14.3 (RP11-291O24-RP11-62E10) × 1 dn Febrile seizure [22] 39 5q14.3-q15 del (3.574 Mb), arr cgh 5q14.3q15 Atypical absences, followed by complex partial seizures [22] (rs10223241 − rs17664587) × 1 dn 40 5q14.3-q21.3 del (17 Mb), GC Chr5:88 945 075–105 929 555 Febrile seizures, followed by generalized tonic–clonic seizures [14] 41 5q14.3-q15 del (8.4 Mb), GC Chr5: 87 086 298–95 538 699 ISS, epileptic spasms [14] 42 5q14.3-q15 del (6.3 Mb), GC Chr5: 88 659 488–94 986 600 Episodes of unresponsiveness, followed by myoclonic seizures [14] Del deletion, GC genomic coordinates, Mb megabase, ISS infantile spasms Zhang and Zhao Molecular Brain (2022) 15:8 Page 6 of 11 hematological tumors, pancreatic cancer or liver cancer, behaviors. Although there are many etiological mod- leading to exhibition of various tumor characteristics els for ASD, such as gene mutations, abnormal synaptic [17]. MEF2C plays an important role in tumor patho- development or signaling pathways, its pathogenesis has genesis and development, however, a limited number of not been conclusively determined. One of the mecha- studies have evaluated its functions in nervous system nisms involved in ASD pathogenesis is the imbalance tumors [21, 78]. in excitatory/inhibitory synaptic ratio [15]. Synaptic A study on brain metastases of breast cancer  (BCBM) formation dominates the early stages of brain develop- demonstrated that MEF2C, as a target gene of miR- ment, resulting in the generation of more synapses than 802-5p and miR-194-5p, is increased in metastatic tumor are needed for brain functions. Consequently, the cells. Immunoreactivity analyses showed that MEF2C brain prunes the extra synapses [27]. MEF2C plays an expression increased by 24% between the 3rd and 10th important role in activity-dependent synaptic elimina- day of brain metastasis (p < 0.001), and by 20% between tion. When depolarization and calcium influx occur in the 7th and 10th day (p < 0.001). Therefore, as a tran - neurons after stimulation, MEF2C is activated, then it scription factor, MEF2C promotes the development of induces the transcription of protocadherin-10 (Pcdh10). metastatic tumors. It was also found that peritumoral Pcdh10 mediates the degradation of synaptic scaffold astrocytes began to express MEF2C after exudation of protein 95 (PSD-95) by binding ubiquitin PSD-95 to the tumor cells from tumor tissues, while non-peritumoral proteasome, leading to elimination of excitatory synapses astrocytes did not show these expressions, suggesting [64, 69]. that MEF2C is involved in the crosstalk between astro- Dysfunctions of the MEF2C gene may prevent the cytes and tumor cells during the development of BCBM  brain from eliminating unwanted excitatory synapses, [61]. leading to ASD-like syndromes (Table  3). A previous In the cytoplasm, MEF2C was shown to impair study reported a significant increase in the number of β-catenin translocation into the nucleus, thereby inhib- excitatory synapses and spinous processes in MEF2C-KO iting Wnt/β-catenin signaling during the early stages of mice, as well as enhancement of basal and evoked synap- metastases development. However, in advanced stages, tic transmission. This cascade of events led to develop - MEF2C and Wnt/β-catenin translocated to the nucleus, ment of hippocampal dependent learning and memory which was accompanied by an increase in Ki-67 positive impairments, as well as ASD-like social behavior defects cells. Continuous expression of MEF2C and its translo- [6]. Conditional MEF2C KO in neural stem/progenitor cation to the nucleus is associated with disease severity, cells expressing Nestin can affect neuronal differentia - and MEF2C may serve as a biomarker for BCBM devel- tion, resulting in abnormal density and cell body sizes of opment and prognosis as well as its potential therapeutic cortical plate neurons, without affecting the proliferation target [24]. as well as survival of neural stem cells. The conditioned The dual role of MEF2C in tumors has also been MEF2C-KO mice that survived to adulthood showed reported in liver cancer. In the nucleus of hepatocellular more immature electrophysiological network charac- carcinoma, MEF2C promoted the invasion and angiogen- teristics and serious behavioral defects, indicating that esis of hepatocellular carcinoma cells, while cytoplasmic MEF2C plays a key role in early programming of neu- MEF2C isolated β-catenin in the cytoplasm and reduced ronal differentiation and distribution of neocortical layers the ability of β-catenin to promote cell proliferation. Sub- in ASD [5]. Unlike the previous thought that MEF2C was cellular distribution of MEF2C may determine the over- only expressed in the cerebral cortex and hippocampus all role of MEF2C [5]. On the other hand, after being [2], recent studies have found that MEF2C was  specifi - assembled into multi-protein complexes as transcrip- cally expressed in the Purkinje cell layer of the cerebrum tion factors, MEF2C can be transformed into transcrip- [32]. It selectively regulates the development of dendrites tion activators or inhibitors under the control of tumor of Purkinje cells and prunes the synapses of climbing fib - microenvironments to produce the opposite effects [44]. ers. Similar with ASD findings, deletion or downregula - Therefore, MEF2C may act as a “double-edged sword” tion of MEF2C resulted in increased dendritic branches (either as a proto-oncogene or a tumor suppressor) in and spines in Purkinje cells, and changes in excitatory as tumor pathogenesis. well as inhibitory synaptic protein localization [37, 39]. Essentially, the increased spines are immature spines that Autism spectrum disorders are most likely to be pruned later, resulting in a decrease Autism spectrum disorders (ASD) are a group of severe in the number of neurons and a decline in overall func- neurodevelopmental disorders that are characterized by tions [45]. impaired social interactions and communication skills, Studies on deletions of MEF2C in frontal brain regions and/or narrow interests and repetitive stereotyped of conditioned MEF2C-KO mice after birth, using Zhang and Zhao Molecular Brain (2022) 15:8 Page 7 of 11 Table 3 Neural phenotype and behavior phenotype in manipulation of MEF2C Sample Neural phenotype Behavior phenotype References Calcium/calmodulin-dependent protein kinase II (CaMKII)- Increased the number of spines in the hippocampus of mice Not related with the presentation of learning and memory, [16] Cre93 line conditioned MEF2C-KO mice after birth LTP or social behavior Late embryonic deletion of MEF2C in the forebrain Increased the number of excitatory synapses and spinous Hippocampus-dependent learning and memory impair- [6] Transgenic expression of a superactive form of MEF2C in processes ment neurons Enhanced basal and evoked synaptic transmission of mice (NSE-MEF2C-VP16 transgenic mice) Reduced structural and functional glutamatergic synapse density in hippocampal pyramidal neurons Conventional exon 2-deleted allele of MEF2 deletion or Increased dendritic branches and spines in Purkinje cells, [37, 39] downregulation of MEF2C and changes in excitatory and inhibitory synaptic protein localization Conditional MEF2C gene KO in neural stem/progenitor cell Abnormal density and cell body size of cortical plate More immature electrophysiological network characteristics [5] neurons and serious behavioral defects Knockdown of MEF2C Reduced the number of dendritic spines on apical dendrites Hyper-sensitive passive avoidance behavior [31] Overexpression of MEF2C of cultured neural progenitor cells Increased spine density Embryonic MEF2C deletion from most forebrain excitatory A ~ twofold increase in dendritic GABAergic synapse density Deficits in fear learning and memory, multiple social [26] neurons in mice (EmxCre × MEF2C flox/flox) on excitatory cortical pyramidal neurons behaviors, socially-motivated ultrasonic vocalizations, and reward-related behaviors HSV-Cre-GFP virus injection in MEF2C flox/flox pups at P2 to Increased in spine counts in SPNs at P8 Defective neonatal isolation-induced USVs, a form of vocal [18] down-regulate MEF2C expression Normal number of dendritic spines in SPNs at P19-20 communication in neonatal rodents HSV-Cre-GFP virus injection in MEF2C flox/flox mice at P14- Decreased number of spines in SPNs at P14 15 to down-regulate MEF2C expression In utero electroporation of pcBIG-Mef2C-VP16 plasmids at E12.5 in wild-type embryos to overexpress MEF 2C Postnatal MEF2C deletion Decreased excitatory synapse number from L4 / L2/3 [56] AAV-Cre-GFP infection in dissociated neocortical cultures pyramidal neurons A reduced spine density on basal of normal dendritic branching in neurons Conventional exon 2-deleted allele of MEF2C Reduced number of neurons and total dendritic lengths Intellectual disability, speech deficit, autism-like symptoms, [70] Dendritic interactions impairment seizures or motor abnormalities Increased E/I ratio in the hippocampus Upregulation of MEF2C in the adult prefrontal cortex (PFC) Decrease in mushroom spines proportion in layer III of the Improved cognition [47] by AAV-MEF2C virus injections PFC with no difference in total spine density SPNs striatal projecting neurons Zhang and Zhao Molecular Brain (2022) 15:8 Page 8 of 11 the calcium/calmodulin-dependent protein kinase II prefrontal lobe are highly associated with disability. In (CaMKII)-Cre93 line, showed that although the number a study involving 150,000 participants, the Psychiatric of spines in the hippocampus of mice increased signifi - Genome Association identified 108 different genome loci cantly, these increases were not related with presentation associated with schizophrenia [51]. There are MEF2C of learning and memory, long-term potentiation (LTP) target sites in the heritable risk factors for schizophrenia, or social behaviors [16]. In spite of continuous roles of which associate MEF2C with this disease. MEF2C in negative regulation of synaptogenesis, the An enrichment of MEF2C motifs in the SNP pool, with functions of MEF2C, which involves the regulation of the top score being related to schizophrenia was reported synaptic plasticity, learning and memory or behavio- [47]. Sequencing data of chromatin-associated histone ral expressions in ASD may depend on expressions of methylation in the prefrontal neuronal chromatin of 17 MEF2C during embryonic development, rather than just schizophrenic patients showed that MEF2C-binding regulation of the number of synapses [1]. motifs were significantly overexpressed in about 1000 There is a significant overlap between the genes regu - nucleosome sequences, affected by histone H3K4 hyper - lated by MEF2C and dozens of candidate ASD risk genes methylation. The hypermethylated sequence of trime - [26]. For instance, ASD-related symptoms have been thyl-histone H3-lysine 4 (H3K4me3) exhibited a strong reported in some patients with MEF2C haploid insuf- neuronal footprint, with 6/12 of Gene Ontological (GO) ficiency syndrome (MCHS) [72]. MCHS, a neurodevel - categories being associated with synapses and neurons, opmental disorder, is caused by microdeletion, missense and 8/18 of “drug” and “phenotypic” categories being or nonsense mutations in the MEF2C gene or copy num- matched with decreased cognition and abnormal behav- ber variations (CNVs). Chromosomal microarray data iors. Down-regulation of MEF2C in cell culture models revealed that MEF2C mutations are scattered throughout showed hypermethylation of H3K4 in affected nucle - the MEF2C protein, without thermal mutation regions. osomes, similar to the changes observed in prefrontal The patients showed varying degrees of intellectual dis - lobes of schizophrenia. Increasing expressions of MEF2C abilities, speech deficits, autism-like symptoms, seizures in the prefrontal lobe of cognitive impaired mice models or motor abnormalities [36]. In general, phenotypic char- with schizophrenia by using adeno-associated virus vec- acteristics of MCHS may present dysplasia of multiple tors significantly improved cognitive abilities. Following nerve cell populations at the transcriptional level, with treatment with the NMDA receptor antagonist, MK-801, ASD syndromes being the most pronounced [57]. the cognitive performance of mice with up-regulated Rett syndrome, one of the serious neurodevelopmen- MEF2C levels were better compared to those of normal tal diseases, which occurs mostly in women. It is char- mice. Therefore, MEF2C transcription factors are prom - acterized by progressive decline in motor skills and ising targets for treatment of schizophrenia-associated intelligence. The MeCP2 mutation allele in region q28 on cognitive impairment [30]. X chromosome has been shown to trigger the Rett syn- drome [38]. Jiaping W et  al. found 3 MEF2C heterozy- gous mutations in 44 patients with the Rett syndrome, Summary without MeCP2 gene mutations, suggesting the MEF2C MEF2C plays a significant role in early brain develop - gene mutation is one of the risk factors for Rett syndrome ment of humans or animals, and in normal develop- [74]. Based on definitive pathogenesis of MeCP2 gene ment, distribution and electrical activity of neocortical mutations, DSM-5 removed Rett syndrome from the neurons. Besides, it has a profound effect on neuropsy - diagnosis of ASD in 2013. However, this change has been chiatric phenotypes. Because of the important effects of questioned by many scholars. Since ASD is diagnosed MEF2C on synapses, MEF2C gene mutations or dysfunc- via language as well as behavioral symptoms and is also tions will lead to a series of syndromes, including intel- caused by genetic variations, it may not remove a subtype lectual deficiency, epilepsy and autism-like symptoms. of ASD when one pathogenic gene is found. According to The association between MEF2C and cognitive impair - current studies, some of the patients diagnosed with Rett ment coincides with the role of MEF2C in AD and ASD. syndromes do not have the MeCP2 gene mutation, but In view of similar symptoms caused by MEF2C defects share common pathogenic genes with ASD. Therefore, in various neuropsychiatric disorders, we recommend more evidence is needed to distinguish Rett syndrome that it be described as MEF2C-related syndrome, which from ASD. would be contribute to identify characteristic gene- related symptoms from these complex neuropsychiatric disorders. 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Journal

Molecular BrainSpringer Journals

Published: Jan 6, 2022

Keywords: MEF2C; Transcription factor; Synapse; Neurodevelopment; Neuropsychiatric disease

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