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Connecting DCX, COMT and FMR1 in social behavior and cognitive impairment

Connecting DCX, COMT and FMR1 in social behavior and cognitive impairment Genetic variants of DCX, COMT and FMR1 have been linked to neurodevelopmental disorders related to intellectual disability and social behavior. In this systematic review we examine the roles of the DCX, COMT and FMR1 genes in the context of hippocampal neurogenesis with respect to these disorders with the aim of identifying important hubs and signaling pathways that may bridge these conditions. Taken together our findings indicate that factors connecting DCX, COMT, and FMR1 in intellectual disability and social behavior may converge at Wnt signaling, neuron migration, and axon and dendrite morphogenesis. Data derived from genomic research has identified a multitude of genes that are linked to brain disorders and developmental differences. Information about where and how these genes function and cooperate is lagging behind. The approach used here may help to shed light on the biological underpinnings in which key genes interface and may prove useful for the testing of specific hypotheses. Keywords: Intellectual disability, Social behavior, Neurogenesis, Hippocampus, Wnt signaling, COMT, DCX, FMR1 could interface at the molecular and cellular level. Our Introduction approach employs a literature review and an assessment The aim of this systematic review is to gain an under - of legacy RNA-Seq datasets to identify genes with cor- standing of the genetic underpinnings linking intellec- relative expression patterns to DCX, COMT, and FMR1 tual disability (ID) and social behavior in the context of in the developing hippocampus [2]. The gene correlates three critical risk factor genes DCX, COMT, and FMR1. were evaluated using integrative genomics methods In the study by Kwan et al. [1] the authors used a method which include an analysis of gene set intersection [3] and similar to ours which involved identifying signaling path- functional enrichment [4]. Additional insight concerning ways associated with Autism Spectrum Disorder (ASD) the relationship between DCX, COMT and FMR1 was and ID based on risk factor genes linked to these disor- obtained by an evaluation of protein–protein interaction ders that were identified in genomic studies. In this study (PPI) networks [5, 6]. we have started with three risk factors genes associated with a multitude of neuro-related disorders and have Hippocampal neurogenesis and Wnt signaling found through a review of the literature that they con- In neurogenesis, neural stem cells proliferate, migrate, verge in Wnt signaling, neuron migration, axon, and den- and differentiate into mature neurons. The production of drite morphogenesis. To provide further insight we use new neurons is most active during development but con- systems biology methods to investigate how these genes tinues throughout life in many species including humans [7, 8]. Hippocampal neurogenesis occurs in the subgran- Emily Xiao and Devika Manoj contributed equally to this work ular zone of the dentate gyrus (DG) in a tightly regulated *Correspondence: anna.delprato@gmail.com and sequential manner [9]. It is well established that dys- 1 regulation of hippocampal neurogenesis is linked to a Department of Research and Education, BioScience Project, Wakefield, MA 01880, USA variety of neurological disorders such as ASD, Fragile-X Full list of author information is available at the end of the article © 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. Delprato et al. Behavioral and Brain Functions (2022) 18:7 Page 2 of 11 Syndrome (FXS) and ID [10–12]. This is not surprising the stability, organization and movement of microtubules given the role of the hippocampus in learning, long term which impairs their ability to move neurons [36]. Migrat- memory, and the processing of emotional response [13]. ing neurons in the developing brain are particularly Hippocampal neurogenesis is regulated by Wnt signal- affected because they are mis-localized which disrupts ing which has been suggested as a conserved feature in connectivity resulting in neurological problems [38]. both embryonic and adult neurogenesis [14–16]. The While the role of doublecortin in microtubule stabili- Wnt signaling pathway regulates cell fate decisions, tissue zation and neuronal migration is well established [39]. patterning, neuronal differentiation, axon outgrowth and There is evidence that doublecortin is also involved in guidance, dendrite development, synaptic function, and axon guidance via actin association and dendrite branch- neuronal plasticity [17, 18]. ing and complexity [35, 40, 41]. Wnt proteins are involved in all aspects of the devel- Dcx knockout mice have a simplified dendrite morphol - oping brain [19]. In neuronal development Wnt proteins ogy in hippocampal pyramidal neurons [37]. Knockdown bind Frizzled receptors, Tyrosine kinase receptors or the of Dcx in cultured rat neurons also led to a simplified Insulin-like growth factor receptor to activate Dishev- dendrite morphology [15, 19]. Conversely, overexpres- elled which results in different fates depending on the sion of doublecortin increases dendrite complexity [37]. cellular context [20]. This includes gene transcription, Interestingly, daily mild stress exposure in mice altered regulation of axon and dendrite morphology and pre dendrite length and complexity in doublecortin positive synaptic function via small GTPases of the Rho family, immature neurons of the dentate gyrus [42]. which in turn modulate neuronal polarity, dendritic spine Several diseases are linked to DCX variants such as morphology and synapses [21, 22]. The Wnt/Dishev - Isolated Lissencephaly Sequence (ILS) which is a disor- elled axis may also proceed through a calcium signaling der characterized by abnormal brain development that pathway or other pathway intermediates to modulate the results in the brain having a smooth surface (lissenceph- guidance and branching of dendrites and axons, as well aly) instead of normal gyri and sulci [43, 44]. This causes as synapse formation and remodeling [20, 23]. There is severe neurological issues such as ID and recurring sei- a great deal of evidence derived from genetically altered zures which begin in infancy. Most of the DCX gene animals, cell based, and human studies supporting the mutations that cause ILS are a result of a single amino role of Wnt signaling in ID and ASD [24–28]. In individ- acid substitution in doublecortin producing a protein uals with ASD, ID varies widely. However, in cases where with little or no function [45]. [29] the two conditions coexist the GSK3 and CTNNB1 Subcortical Band Heterotopia (SBH) is another disor- genes are strongly implicated [26, 30, 31]. The CTNNB1 der associated with mutation in the DCX gene [46]. This gene, which encodes β-catenin, is a main modulator of condition causes abnormal brain development that is the canonical Wnt signaling pathway and is linked to less severe than ILS but has a similar pathology. In peo- sporadic ASD and ID [1, 29, 32]. In mice, a conditional ple with subcortical band heterotopia, some neurons knockout of Ctnnb1 deleted in parvalbumin interneu- that should be part of a certain region of the brain do not rons significantly impaired object recognition and social reach their destination [47]. Neurons stop their migra- interactions and increased repetitive behaviors [24]. tion process in areas of the brain where they are not sup- Moreover, data derived from large scale exome sequenc- posed to be and form band-like clusters of tissue. Male ing studies investigating ASD and ID have identified non - and female differences have been noted in lissencephaly sense and missense mutations in CTNNB1 [30, 33]. and SBH related to DCX mutations which predominantly causes lissencephaly in hemizygous males and SBH in heterozygous females. Both males and females exhibit DCX, FMR1, and COMT in hippocampal neurogenesis language impairment and epileptic seizures however cog- i. Role of DCX in hippocampal neurogenesis and disease nitive ability varies between the two sexes. Males exhibit The DCX gene product, doublecortin, stabilizes micro- early and severe cognitive impairment whereas cognitive tubules and stimulates their polymerization to facilitate ability ranges from mild to severe in females [48, 49]. the migration of post mitotic neurons and cortical lay- ering in the developing brain [34]. Doublecortin acts via microtubules to form a scaffold within the cell that ii. Role of COMT in hippocampal neurogenesis and disease elongates in a specific direction, altering the cytoskel - The COMT gene encodes the enzyme, catechol-O-meth- eton and moving the neuron to a targeted location [35, yltransferase which catalyzes the transfer of a methyl 36]. Doublecortin is used as a neuronal differentiation group from S-adenosylmethionine to catecholamines in and migration marker to assess the various stages of the several neurotransmitters such as dopamine, epineph- neurogenic process in the sub granular zone (SGZ) of the rine, and norepinephrine. This O-methylation results in hippocampus [37]. A lack of normal doublecortin affects D elprato et al. Behavioral and Brain Functions (2022) 18:7 Page 3 of 11 one of the major degradative pathways of the catechola- alter GSK3 signaling. GSK3 phosphorylates CTNNB1 mine transmitters. resulting in its degradation and the down regulation of COMT has both soluble and membrane-bound iso- the Wnt signal [66]. forms and is expressed in many different tissues. The COMT is also associated with 22q11.2 Deletion Syn- membrane bound form (MB-COMT) has a preference drome which results from a deletion of a region of chro- for brain tissue and especially the hippocampus [50]. mosome 22 that contains 30–40 genes [58]. Learning MB-COMT is located on axons and neuron cell bod- disabilities and psychiatric disturbances such as ASD, ies in pre and postsynaptic structures [51]. Analyses of schizophrenia, and attention deficit hyperactivity disor - MB-COMT orientation with computer simulation, flow der (ADHD) are associated with 22q11.2 Deletion Syn- cytometry, and a cell surface enzyme assay indicates that drome [67, 68]. the C-terminal catalytic domain of MB-COMT is in the Individuals with this disorder have only one copy of extracellular space, which suggests that MB-COMT can the COMT gene in each cell instead of the usual two cop- inactivate synaptic and extrasynaptic dopamine on the ies making them more likely to develop neuropsychiat- surface of presynaptic and postsynaptic neurons [51]. ric disorders. COMT variants and dopamine levels have MB-COMT is expressed by postsynaptic neurons and/ been linked to ASD [69]. In a study of 52 individuals or surrounding glia (Gogos et al. 1998; Schott et al. 2010; diagnosed with ASD, COMT genotypes and dopamine Rivett et  al. 1983b; Karhunen et  al. 1995a; Matsumoto levels correlated with ASD phenotype severity [69]. In et  al. 2003) where it modulates synaptic dopamine lev- another study investigating dopaminergic effects in two els. Dopamine levels are increased by as much as 60% mouse models of ASD, differential expression of tyrosine in Comt knock-out mice [7] (e.g., Chen et  al. 2004; Leb- hydroxylase (TH), the rate-limiting enzyme of catecho- edeva et al. 2009; Grigorenko et al. 2007). lamine biosynthesis, was observed between the strains. COMT localization has also been observed in den- There was a reduction of TH in BTBR/J mice and normal drites [51, 52] Localization of COMT in rats using immu- levels in Fmr1-KO animals. Striatal dopamine transporter noelectron microscopy results in the presence of reaction expression was reduced in both strains. Interestingly, product in dendritic processes and spines associated application of intranasal dopamine to Fmr1-KO animals with postsynaptic membranes [50]. COMT is particu- alleviated their impairment of social novelty, in altered larly important in the prefrontal cortex, the region of association with reduced striatal TH [70]. (https:// the brain associated with personality, executive func- mole c ul arb rain. biome dc en t ral. c om/ ar tic le s/ 10. 1186/ tion, inhibition of behaviors, abstract thinking, emotion, s13041- 020- 00649-7). and working memory [53, 54]. Several studies have also Besides schizophrenia, ID, and ASD, COMT function demonstrated its relevance in the hippocampus [55–57] in the context of dopamine regulation is also associated and neurogenesis [53, 58, 59]. Copy number elevation of with addiction and depression [71–73]. COMT is associated with reduced proliferation of neural stem/progenitor cells in  vitro and the migration of their iii. Role of FMR1 in hippocampal neurogenesis and disease progeny in the hippocampus granular layer in  vivo [58] The FMR1 gene encodes the FMRP protein. Results as well as hippocampal volume changes in the CA2/CA3 from many years of research indicate that FMRP acts as regions [59]. The COMT genotype influenced the matu - a transporter carrying mRNA from the nucleus to areas ration of working memory associated with problem solv- of the cell where proteins are assembled [74]. Altered ing and knowledge acquisition skills in both mice and neurogenesis has been reported in an Fmr1-/-knockout humans [40, 41]. mouse model. Animals displayed an increase in neuronal COMT and Wnt signaling are both linked to schizo- differentiation in the DG but no significant difference in phrenia which has been postulated to arise from abnor- the number of neurons added to the DG [12]. The con - mal neurogenesis associated with embryonic neural stem nection between FMR1 and Wnt signaling is supported cells [60–62]. The relationship between COMT and Wnt by the finding that GSK3β, a negative regulator of Wnt signaling in the context of neurogenesis may be based signaling, is elevated in FXS animal models [65]. Cor- on dopamine regulation. The COMT gene has long been rection of the increased GSK3 activity with lithium or considered a candidate gene for schizophrenia because GSK3β inhibitors in mice rescues neurobehavioral and it degrades dopamine and individuals with schizophre- brain morphological abnormalities [75]. Furthermore, nia have increased dopamine levels [63]. Wnt signal- inhibition of GSK3β is reported to improve hippocam- ing is associated with schizophrenia, particularly via the pus-dependent spatial learning tasks and restore neuro- GSK3 gene which acts downstream of the dopamine (D2) genesis in a mouse model of FXS [65]. receptor [64, 65]. Drugs that induce psychosis increase FMRP localizes to axons and dendrites [76]. Studies D2 receptors and drugs that are used to treat psychosis involving both humans and mice support the role of Delprato et al. Behavioral and Brain Functions (2022) 18:7 Page 4 of 11 Network analysis FMRP expression in normal spine morphological devel- The String database (version 11.0) was used to build a opment [77, 78]. The data obtained from human post protein–protein interaction network (PPI) for DCX, mortem tissue derived from donors with FXS and ani- COMT, and FMRP [5, 88]. The network was constructed mal models in which FMRP is underexpressed or not based on experimentally validated interactions using the expressed at all indicate an increase in spine density, medium confidence score of 0.4. The combined scores spine length and immature spine morphology [76, 79]. for the interactions are computed by combining the FMRP has an inhibitory effect on mRNA transla- probabilities from the different evidence channels and tion and regulates translation in pre- and post-synaptic corrected for the probability of randomly observing an terminals [80]. A possible explanation of the effects of interaction. First and 2nd shell interactions are included FMRP in spine dynamics and morphology is by influ- in the network. The network was exported from STRING encing local mRNA translation [81]. A trinucleotide and analyzed in Cytoscape (version 3.7) [6, 89]. Net- repeat mutation in the FMR1 gene is the underly- work clusters and enriched themes were identified with ing cause of FXS [82]. The CGG repeat disrupts gene Cytoscape plugins MCODE (version 1.6.1) and ClueGo expression and as a consequence little or no protein (version 2.5.7) [4, 90]. The nodes in the networks have is produced [82]. FXS is one of the most commonly been manually arranged for proper visibility. inherited forms of ID and monogenic causes of ASD [83, 84]. Results Methods To investigate how these genes may interact we per- Literature review formed a literature review which supported that Wnt The literature review for identifying common themes signaling, neuron migration, and axon and dendrite mor- associated with DCX, COMT, and FMR1 was per- phogenesis were common factors in connecting DCX, formed using PubMed, Google Scholar, and the Online COMT, and FMR1 in ID and social behavior. Based on the Mendelian Inheritance in Man database [85]. Reposi- results of the literature review, we examined RNA-Seq tories and databases were searched using keywords datasets of genes with correlating expression patterns to associations. DCX, COMT, and FMR1 in the developing hippocampus in order to gain further insight. GO annotation was used to identify gene correlates associated with Wnt signal- ing, neurogenesis, social behavior, and ID. Among the Gene sets and evaluation correlates, many genes are linked to Wnt signaling, neu- Microarray data were collected from the Allen Brain rogenesis, and ID and to a lesser extent social behavior Database Developing Human Brain Atlas (https:// (Tables 1, 2, 3, 4). All of the results from the GO analysis human. brain- map. org/, https:// human. brain- map. org/). which includes biological processes, cellular localization, To obtain the data, a gene search for DCX, COMT, molecular function, as well as pathway and disease infor- and FMR1 was performed. Each of these genes were mation are provided in Additional file 2: Workbook S2. used to query the atlas for correlates to the developing The results from the analyses of gene set overlap which hippocampus. was performed to shed light on how these genes might Genes whose expression pattern correlated with DCX, interact at the molecular level, consisted of identifying COMT, and FMR1 were collected for analysis. Correlates common genes among the correlates for DCX, COMT, with a range of Pearson r values from |0.7 to 1.0| were and FMR1. Findings indicate that there were many considered in the analysis (Additional file  1: Workbook shared relevant genes inversely correlated with COMT, S1). The rationale was to investigate genes with a similar DCX, and FMR1 expression patterns particularly in the expression pattern in order to identify correlates specific context of ID (CHAMP1, DCHS1, EML1, MCPH, TCF4, and common to DCX, COMT, and FMR1 associated with CTCF, FAT4, FXR2, GATAD2B, KIAA2022, SETBP1, neurogenesis, Wnt signaling, ID, and social behavior. TAF2, BCAP31, BRWD3, NUFIP1, ATRX) and to a lesser Each gene set was evaluated using Gene Ontology extent social behavior (AUTS2, PCM1). Other shared (GO) enrichment via the Database for Annotation, Visu- correlating genes with relevance are linked to neurogen- alization and Integrated Discovery (DAVID, version 6.8) esis, Wnt signaling, transcription regulation, microtubule [86]. Gene Set overlap among the correlates for DCX, and axon related processes (Table 5 and Additional file  2: COMT, and FMR1 was assessed using Venny 2.0 [87], an Workbook S2). online program that compares lists of items to determine The majority of ID related genes are shared between the shared and unique genes. DCX positive and COMT negative correlates. A possible D elprato et al. Behavioral and Brain Functions (2022) 18:7 Page 5 of 11 Table 1 Wnt pathway genes associated with DCX, COMT and FMR1 correlates in the hippocampus DCX + ACTB, ACTG1, ACVR1B, ARID1A, ARID1B, BCL9, CDH2, CELSR3, CSNK1E, CSNK1G1, CSNK2A1, DACT1, DCHS1, FAT4, FZD7, GNB1, GNG2, HDAC2, MYCN, PCDHB12, PCDHB14, PCDHB2, PCDHB8, PCDHB9, PPP2R5E, PYGO1, SIAH1, SMAD1, SMAD4, SMARCA4, SMARCB1, SMARCD1 DCX − CDH19, DCHS1, GNA14, GNA15, GNG13, GNG7, KREMEN2, MYH13, MYH7B, WNT10A, WNT6, WNT9B COMT + BMPR1B, GNA14, ITPR3, KREMEN2, NFATC1, NFATC2 PPARD, PPP2R5A, SMARCD2, TCF7 COMT − CELSR3, CSNK1G1, CSNK1G3, DACT1, FAT4, GSK3B, HDAC2, MAP3K7, PCDHB3, PPP2R5E, PRKCI FMR1 + LRP6, PPP2CA, PRKCI, SMARCA5, TBL1XR1 FMR1 − DVL1, DVL1P1 Positive and negative associations are indicated with “+” and “−” respectively Table 2 DCX, COMT and FMR1 gene correlates associated with intellectual disability DCX + ACTB, ACTG1, ADNP, ARID1A, ARID1B, AUTS2, BBS9, CASK, CHAMP1, CTCF, DCHS1, DYRK1A, EDC3, EFTUD2, EHMT1, EML1, EXT2, FAT4, FGD1, FOXG1, FRMD4A, FTSJ1, FXR2, GATAD2B, GNB1, IGBP1, KAT6A, KIAA2022, LMAN2L, MCPH1, NONO, OPHN1, POGZ, RBMX, RSPRY1, SETBP1, SMARCA4, SMARCB1, SMC3, SOX11, TAF2, TCF4, TTI2, TUBGCP4, ZC4H2, ZEB2, ZNF711 DCX − BCAP31, MAP2K1 COMT + BCAP31, CHI3L2, CLIC2, HEPACAM, PGAP3, PIGV, PPIC, SLC6A8, TECR, VWA3B COMT − ATP8A2, ATRX, AUTS2, BRWD3, CHAMP1, CTCF, DDX3X, EML1, FAT4, FXR2, GATAD2B, KDM6A, KIAA2022, MCPH1, MED13L, NUFIP1, PAK3, PGAP1, SETBP1, SOX5, TAF2, TCF4, T TC21B, UPF3B FMR1 + AMMECR1, ATRX, BRWD3, COG6, CRBN, CUL4B, FMR1, KIAA0196, KIAA1033, NIPBL, NUFIP1, NUFIP2, RAB3GAP2, RAD21, RBBP8, RPS6KA3, TBL1XR1, TDP2, T TC21B, USP9X, ZDHHC15 FMR1 − No associated genes Positive and negative associations are indicated with “+” and “−” respectively Table 3 DCX, COMT and FMR1 gene correlates associated with Table 4 DCX, COMT and FMR1 neurogenesis related gene social behavior correlates DCX + DNAJC9, AUTS2, EIF4, EBP2 DCX + AKT1, ARID1A, ARID1B, BCL11B, BZW2, CEP120, DACT1, DBN1, DCHS1, DOCK7, DPYSL2, DYNLT1, EFNB2, EPHB1, DCX − SHANK3, ANXA7, MYH14, NPAS4 EPHB2, FAT4, FOXN4, GPSM1, IGSF9, INA, INSM1, ISLR2, COMT + DRD4, UCN KDM1A, KIAA2022, KIDINS220, NEUROD2, NGFR, OPHN1, COMT − KRAS, AUTS2, PCM1 RBM45, SEMA3A, SEMA3C, SEMA4C, SMARCA4, SMARCB1, SMARCD1, SOX11, SRGAP2, STMN1, TCF4, XRCC5 FMR1 + PCM1 DCX − BCL6, CHN1, CIT, GLDN, HAP1, NPAS4, NTRK1, PAX5 FMR1 − DVL1 COMT + BCL6, CSPG5, HAP1, METRN, MT3, NDRG2, PLXNB3, SIRT2, Positive and negative associations are indicated with “ + ” and “-” respectively ZC3H12A COMT − ARHGEF2, BCL11B, BHLHB9, BZW2, CEP120, DACT1, EFNB2, EIF2AK4, EPHA4, EPHA7, FAT4, FBXO45, GSK3B, explanation could be related to the roles of COMT and KIAA2022, KIDINS220, KIF2A, NEUROD6, PCM1, PRDM8, ROBO2, SEMA3A, SEMA3C, SPAST, STMN1, TCF4, XRCC5 DCX and their effects on brain structure and neurogene - FMR1 + CCDC88A, EIF2AK4, HOOK3, IMPACT, PCM1, PHF10 sis. In patients with schizophrenia the COMT Val allele is SETX, ZEB1 associated with smaller temporal and frontal brain areas FMR1 − RFNG [91] and as described in the Introduction, DCX variants Positive and negative associations are indicated with “+” and “−” respectively cause severe lamination defects in the cortical and hip- pocampus regions [92]. In addition, there is supporting evidence that increased dopamine neurotransmission interactions for DCX, COMT, and FMRP was per- stimulates neurogenesis [93, 94]. formed. An assessment of network topology and con- The shared genes between COMT and FMR1 are also nectivity indicates that the individual PPI networks for inversely correlated and are associated with similar rel- these genes connect (Fig. 1, Additional file  3: Workbook evant themes (Table  5). There were no relevant genes S3). common between FMR1 and DCX. The DCX and FMRP networks are more highly inter - To gain further insight, an analysis of protein–pro- connected via proteins associated with RNA binding tein interaction networks of experimentally validated and cell cycle such as FXR1/2 and CYFIP2, whereas the Delprato et al. Behavioral and Brain Functions (2022) 18:7 Page 6 of 11 Table 5 Relevant shared gene correlates for DCX, COMT and FMR1 COMT +/DCX − BCAP31 Apoptosis, ubiquitin dependent catabolic process protein transport, X-linked mental retardation, dystonia, cerebral hypomyelination BCL11B Neurogenesis, axon guidance, neuron projection, transcription, splicing, methylation GNA14 Signal transduction phospholipase C-activating dopamine receptor signaling pathway HAP1 Synaptic transmission axonal transport, cerebellum development, cell projection organization, neurogenesis, transport along micro- tubules KREMEN2 Wnt signalling COMT −/DCX + AUTS2 Transcription regulation, Autism, mental retardation/ID BZW2 Nervous system development, cell–cell adhesion, neurogenesis CELSR3 Neuron migration, axonal fasciculation, dopaminergic serotonergic neuron axon guidance, Wnt signaling pathway CEP120 Regulation of centrosome duplication, cerebral cortex development, neurogenesis, astral microtubule organization CHAMP1 Protein localization to kinetochore, protein localization to microtubule, attachment of mitotic spindle microtubules to kinetochore CSNK1G1 Endocytosis, regulation of cell shape, Wnt and Hedgehog signaling CTCF Transcription regulation, DNA methylation, mental retardation, Mental retardation, autosomal dominant 21 DACT1 Transcription regulation, Wnt signaling EFNB2 Cell adhesion, axon guidance, neurogenesis EML1 Microtubule cytoskeleton organization, epilepsy, mental retardation FAT4 Neurogenesis, cerebral cortex development, cell adhesion, mental retardation/ID FXR2 RNA transport, negative regulation of translation, Fragile X mental retardation GATAD2B Transcription, DNA methylation, mental retardation/ID HDAC2 Transcription regulation, chromatin remodeling neuron projection and dendrite development KIAA2022 Nervous system development, X-linked mental retardation, neurogenesis mental retardation, X-linked 98, neurite extension and migration KIDINS220 Dendrite morphogenesis, neuron projection development, neurogenesis MCPH1 Mitotic spindle orientation, regulation of gene expression, cerebral cortex development, mental retardation, Microcephaly 1, pri- mary, autosomal recessive SEMA3A Neuron migration, axon guidance, neurogenesis SEMA3C Neuron migration, axon guidance, neurogenesis SETBP1 DNA binding, Schinzel-Giedion midface retraction syndrome, mental retardation, autosomal dominant 29 STMN1 Microtubule depolymerization, mitotic spindle organization, axongenesis, neurogenesis TAF2 Transcription regulation, mental retardation/ID Mental retardation, autosomal recessive 40 TCF4 Transcription regulation, neurogenesis, epilepsy, mental retardation, Pitt-Hopkins syndrome XRCC5 Transcription, DNA recombination, neurogenesis FMR1 +/COMT − ATRX DNA methylation, chromatin remodeling, transcription, Mental retardation: alpha-thalassemia/mental retardation syndrome, mental retardation-hypotonic facies syndrome, X-linked 52/intellectual development disorder BRWD3 Transcription regulation, mental retardation X-linked intellectual developmental disorder EIF2AK4 Translation, ribosome structure and biogenesis, learning and long-term memory NUFIP1 RNA processing, transcription fragile X mental retardation-interacting protein 1 PCM1 Neuron migration, microtubule organization and anchoring, social behavior, negative regulation of neurogenesis T TC21B Transcription regulator, smoothened signaling pathway regulation FMR1 −/COMT + GAS6 Dendritic cell differentiation, apoptosis KIF19 Axon, microtubule depolymeriation NDUFS7 Synapse, neuron projection Positive and negative correlative gene expression patterns are indicated with “+” and “−” respectively D elprato et al. Behavioral and Brain Functions (2022) 18:7 Page 7 of 11 Fig. 1 DCX, COMT, and FMRP PPI network. A topological evaluation of PPI networks of DCX, COMT, and FMRP indicates that DCX and FMRP networks are highly interconnected, whereas the COMT network is peripherally associated with the DCX network through second shell interactions. Red lines represent first shell interactions which are proteins directly associated with DCX, COMT, and FMRP. Gray lines indicate second shell interactions which are proteins linked with the other proteins in the first shell i.e., not DCX, COMT, or FMR1P COMT network is linked to the DCX and FMRP net- well as several other relevant classifications (Fig.  2 and works via the neurotrophic factor S100B which enhances Additional file 4: Workbook S4). hippocampal neurogenesis in rodent models, as well as the microtubule associated proteins MAPT, which pro- Conclusions motes microtubule assembly and stability and TUBA1A Polymorphisms in the DCX, COMT, and FMR1 genes which is a fundamental component of microtubules are associated with severe and diverse brain develop- [95–98]. ment and neuropsychiatric disorders. Each of these Assignment of over-represented themes based on GO genes has been linked to ID and social behavior. To and pathway analysis of the PPI network modules are: investigate how these genes may interact we performed Module 1. RNA process translation initiation elongation, a literature review which pointed to Wnt signaling, Module 2. Microtubule tubulin cytoskeleton cell cycle, neuron migration, and axon and dendrite morphogen- Module 3. Mitogenic cell survival embryonic develop- esis as common factors. ment cell growth morphogenesis tissue repair, Module Based on the results from the literature review, we 4. Anaphase cell cycle mitotic, cell division and ubiq- analyzed gene expression patterns in the developing uitin processes, Module 5. Actin polymerization cell hippocampus to gain additional support and insight migration, Module 6. Nuclear transport, RNA processes into the relationship between these genes in the con- (Fig. 1). text of identifying molecular interactions and signaling An analysis of neurogenesis related genes from the pathways that may connect them. The findings from DCX, COMT, and FMR1 correlates in the context of these analyses support the results obtained from the enriched functional categories results in thirty-two literature review and provide useful information for fol- groups and within those groups one hundred and ninety- low up studies. one GO annotations. Among the categories there are many related to axon, dendrite, and neuron processes as Delprato et al. Behavioral and Brain Functions (2022) 18:7 Page 8 of 11 Fig. 2 Functional enrichment of DCX, COMT, and FMRP correlates linked to neurogenesis Neurogenesis related gene correlates were further evaluated for functional associations in the context of biological process and pathway integration. Enriched themes include axon guidance, axiogenesis, cell projection and dendritic processes. Red stars indicate functional enrichment themes with particular relevance to the study. Colors are chosen arbitrarily for distinction and to depict overlap. Availability of data and materials Supplementary Information All data are provided with the manuscript. The online version contains supplementary material available at https:// doi. org/ 10. 1186/ s12993- 022- 00191-7. Declarations Additional file 1: Workbook S1. DCX, COMT , and FMR1 hippocampal Ethics approval and consent to participate gene correlates. Not applicable. Additional file 2: Workbook S2. Gene Ontology analysis of DCX, COMT , and FMR1 hippocampal gene correlates. Consent for publication Additional file 3: Workbook S3. DCX, COMT, and FMRP protein–protein Not applicable. interaction network. Competing interests Additional file 4: Workbook S4. DCX, COMT , and FMR1 functional enrich- Not applicable. ment categories for neurogenesis genes. Author details Department of Research and Education, BioScience Project, Wakefield, MA Acknowledgements 01880, USA. Alexander Mackenzie High School, Richmond Hill, ON 14519, Not applicable. Canada. Lambert High School, Suwanee, GA 30024, USA. Authors’ contributions Received: 4 June 2021 Accepted: 14 March 2022 All authors conducted the study, analyzed the data, and wrote and reviewed the manuscript. AD designed and supervised the study. EX and DM con- tributed equally to this study. All the authors read and approved the final manuscript. References Funding 1. Kwan V, Unda BK, Singh KK. Wnt signaling networks in autism spectrum This work was supported by the BioScience Project Research and Education disorder and intellectual disability. J Neurodev Disord. 2016;5(8):45. Organization. 2. Jones AR, Overly CC, Sunkin SM. The Allen Brain Atlas: 5 years and beyond. Nat Rev Neurosci. 2009;10(11):821–8. D elprato et al. Behavioral and Brain Functions (2022) 18:7 Page 9 of 11 3. Conway JR, Lex A, Gehlenborg N. UpSetR: an R package for the intellectual disability with gender-specific effects on Wnt signaling. Am J visualization of intersecting sets and their properties. Bioinformatics. 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Connecting DCX, COMT and FMR1 in social behavior and cognitive impairment

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Abstract

Genetic variants of DCX, COMT and FMR1 have been linked to neurodevelopmental disorders related to intellectual disability and social behavior. In this systematic review we examine the roles of the DCX, COMT and FMR1 genes in the context of hippocampal neurogenesis with respect to these disorders with the aim of identifying important hubs and signaling pathways that may bridge these conditions. Taken together our findings indicate that factors connecting DCX, COMT, and FMR1 in intellectual disability and social behavior may converge at Wnt signaling, neuron migration, and axon and dendrite morphogenesis. Data derived from genomic research has identified a multitude of genes that are linked to brain disorders and developmental differences. Information about where and how these genes function and cooperate is lagging behind. The approach used here may help to shed light on the biological underpinnings in which key genes interface and may prove useful for the testing of specific hypotheses. Keywords: Intellectual disability, Social behavior, Neurogenesis, Hippocampus, Wnt signaling, COMT, DCX, FMR1 could interface at the molecular and cellular level. Our Introduction approach employs a literature review and an assessment The aim of this systematic review is to gain an under - of legacy RNA-Seq datasets to identify genes with cor- standing of the genetic underpinnings linking intellec- relative expression patterns to DCX, COMT, and FMR1 tual disability (ID) and social behavior in the context of in the developing hippocampus [2]. The gene correlates three critical risk factor genes DCX, COMT, and FMR1. were evaluated using integrative genomics methods In the study by Kwan et al. [1] the authors used a method which include an analysis of gene set intersection [3] and similar to ours which involved identifying signaling path- functional enrichment [4]. Additional insight concerning ways associated with Autism Spectrum Disorder (ASD) the relationship between DCX, COMT and FMR1 was and ID based on risk factor genes linked to these disor- obtained by an evaluation of protein–protein interaction ders that were identified in genomic studies. In this study (PPI) networks [5, 6]. we have started with three risk factors genes associated with a multitude of neuro-related disorders and have Hippocampal neurogenesis and Wnt signaling found through a review of the literature that they con- In neurogenesis, neural stem cells proliferate, migrate, verge in Wnt signaling, neuron migration, axon, and den- and differentiate into mature neurons. The production of drite morphogenesis. To provide further insight we use new neurons is most active during development but con- systems biology methods to investigate how these genes tinues throughout life in many species including humans [7, 8]. Hippocampal neurogenesis occurs in the subgran- Emily Xiao and Devika Manoj contributed equally to this work ular zone of the dentate gyrus (DG) in a tightly regulated *Correspondence: anna.delprato@gmail.com and sequential manner [9]. It is well established that dys- 1 regulation of hippocampal neurogenesis is linked to a Department of Research and Education, BioScience Project, Wakefield, MA 01880, USA variety of neurological disorders such as ASD, Fragile-X Full list of author information is available at the end of the article © 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. Delprato et al. Behavioral and Brain Functions (2022) 18:7 Page 2 of 11 Syndrome (FXS) and ID [10–12]. This is not surprising the stability, organization and movement of microtubules given the role of the hippocampus in learning, long term which impairs their ability to move neurons [36]. Migrat- memory, and the processing of emotional response [13]. ing neurons in the developing brain are particularly Hippocampal neurogenesis is regulated by Wnt signal- affected because they are mis-localized which disrupts ing which has been suggested as a conserved feature in connectivity resulting in neurological problems [38]. both embryonic and adult neurogenesis [14–16]. The While the role of doublecortin in microtubule stabili- Wnt signaling pathway regulates cell fate decisions, tissue zation and neuronal migration is well established [39]. patterning, neuronal differentiation, axon outgrowth and There is evidence that doublecortin is also involved in guidance, dendrite development, synaptic function, and axon guidance via actin association and dendrite branch- neuronal plasticity [17, 18]. ing and complexity [35, 40, 41]. Wnt proteins are involved in all aspects of the devel- Dcx knockout mice have a simplified dendrite morphol - oping brain [19]. In neuronal development Wnt proteins ogy in hippocampal pyramidal neurons [37]. Knockdown bind Frizzled receptors, Tyrosine kinase receptors or the of Dcx in cultured rat neurons also led to a simplified Insulin-like growth factor receptor to activate Dishev- dendrite morphology [15, 19]. Conversely, overexpres- elled which results in different fates depending on the sion of doublecortin increases dendrite complexity [37]. cellular context [20]. This includes gene transcription, Interestingly, daily mild stress exposure in mice altered regulation of axon and dendrite morphology and pre dendrite length and complexity in doublecortin positive synaptic function via small GTPases of the Rho family, immature neurons of the dentate gyrus [42]. which in turn modulate neuronal polarity, dendritic spine Several diseases are linked to DCX variants such as morphology and synapses [21, 22]. The Wnt/Dishev - Isolated Lissencephaly Sequence (ILS) which is a disor- elled axis may also proceed through a calcium signaling der characterized by abnormal brain development that pathway or other pathway intermediates to modulate the results in the brain having a smooth surface (lissenceph- guidance and branching of dendrites and axons, as well aly) instead of normal gyri and sulci [43, 44]. This causes as synapse formation and remodeling [20, 23]. There is severe neurological issues such as ID and recurring sei- a great deal of evidence derived from genetically altered zures which begin in infancy. Most of the DCX gene animals, cell based, and human studies supporting the mutations that cause ILS are a result of a single amino role of Wnt signaling in ID and ASD [24–28]. In individ- acid substitution in doublecortin producing a protein uals with ASD, ID varies widely. However, in cases where with little or no function [45]. [29] the two conditions coexist the GSK3 and CTNNB1 Subcortical Band Heterotopia (SBH) is another disor- genes are strongly implicated [26, 30, 31]. The CTNNB1 der associated with mutation in the DCX gene [46]. This gene, which encodes β-catenin, is a main modulator of condition causes abnormal brain development that is the canonical Wnt signaling pathway and is linked to less severe than ILS but has a similar pathology. In peo- sporadic ASD and ID [1, 29, 32]. In mice, a conditional ple with subcortical band heterotopia, some neurons knockout of Ctnnb1 deleted in parvalbumin interneu- that should be part of a certain region of the brain do not rons significantly impaired object recognition and social reach their destination [47]. Neurons stop their migra- interactions and increased repetitive behaviors [24]. tion process in areas of the brain where they are not sup- Moreover, data derived from large scale exome sequenc- posed to be and form band-like clusters of tissue. Male ing studies investigating ASD and ID have identified non - and female differences have been noted in lissencephaly sense and missense mutations in CTNNB1 [30, 33]. and SBH related to DCX mutations which predominantly causes lissencephaly in hemizygous males and SBH in heterozygous females. Both males and females exhibit DCX, FMR1, and COMT in hippocampal neurogenesis language impairment and epileptic seizures however cog- i. Role of DCX in hippocampal neurogenesis and disease nitive ability varies between the two sexes. Males exhibit The DCX gene product, doublecortin, stabilizes micro- early and severe cognitive impairment whereas cognitive tubules and stimulates their polymerization to facilitate ability ranges from mild to severe in females [48, 49]. the migration of post mitotic neurons and cortical lay- ering in the developing brain [34]. Doublecortin acts via microtubules to form a scaffold within the cell that ii. Role of COMT in hippocampal neurogenesis and disease elongates in a specific direction, altering the cytoskel - The COMT gene encodes the enzyme, catechol-O-meth- eton and moving the neuron to a targeted location [35, yltransferase which catalyzes the transfer of a methyl 36]. Doublecortin is used as a neuronal differentiation group from S-adenosylmethionine to catecholamines in and migration marker to assess the various stages of the several neurotransmitters such as dopamine, epineph- neurogenic process in the sub granular zone (SGZ) of the rine, and norepinephrine. This O-methylation results in hippocampus [37]. A lack of normal doublecortin affects D elprato et al. Behavioral and Brain Functions (2022) 18:7 Page 3 of 11 one of the major degradative pathways of the catechola- alter GSK3 signaling. GSK3 phosphorylates CTNNB1 mine transmitters. resulting in its degradation and the down regulation of COMT has both soluble and membrane-bound iso- the Wnt signal [66]. forms and is expressed in many different tissues. The COMT is also associated with 22q11.2 Deletion Syn- membrane bound form (MB-COMT) has a preference drome which results from a deletion of a region of chro- for brain tissue and especially the hippocampus [50]. mosome 22 that contains 30–40 genes [58]. Learning MB-COMT is located on axons and neuron cell bod- disabilities and psychiatric disturbances such as ASD, ies in pre and postsynaptic structures [51]. Analyses of schizophrenia, and attention deficit hyperactivity disor - MB-COMT orientation with computer simulation, flow der (ADHD) are associated with 22q11.2 Deletion Syn- cytometry, and a cell surface enzyme assay indicates that drome [67, 68]. the C-terminal catalytic domain of MB-COMT is in the Individuals with this disorder have only one copy of extracellular space, which suggests that MB-COMT can the COMT gene in each cell instead of the usual two cop- inactivate synaptic and extrasynaptic dopamine on the ies making them more likely to develop neuropsychiat- surface of presynaptic and postsynaptic neurons [51]. ric disorders. COMT variants and dopamine levels have MB-COMT is expressed by postsynaptic neurons and/ been linked to ASD [69]. In a study of 52 individuals or surrounding glia (Gogos et al. 1998; Schott et al. 2010; diagnosed with ASD, COMT genotypes and dopamine Rivett et  al. 1983b; Karhunen et  al. 1995a; Matsumoto levels correlated with ASD phenotype severity [69]. In et  al. 2003) where it modulates synaptic dopamine lev- another study investigating dopaminergic effects in two els. Dopamine levels are increased by as much as 60% mouse models of ASD, differential expression of tyrosine in Comt knock-out mice [7] (e.g., Chen et  al. 2004; Leb- hydroxylase (TH), the rate-limiting enzyme of catecho- edeva et al. 2009; Grigorenko et al. 2007). lamine biosynthesis, was observed between the strains. COMT localization has also been observed in den- There was a reduction of TH in BTBR/J mice and normal drites [51, 52] Localization of COMT in rats using immu- levels in Fmr1-KO animals. Striatal dopamine transporter noelectron microscopy results in the presence of reaction expression was reduced in both strains. Interestingly, product in dendritic processes and spines associated application of intranasal dopamine to Fmr1-KO animals with postsynaptic membranes [50]. COMT is particu- alleviated their impairment of social novelty, in altered larly important in the prefrontal cortex, the region of association with reduced striatal TH [70]. (https:// the brain associated with personality, executive func- mole c ul arb rain. biome dc en t ral. c om/ ar tic le s/ 10. 1186/ tion, inhibition of behaviors, abstract thinking, emotion, s13041- 020- 00649-7). and working memory [53, 54]. Several studies have also Besides schizophrenia, ID, and ASD, COMT function demonstrated its relevance in the hippocampus [55–57] in the context of dopamine regulation is also associated and neurogenesis [53, 58, 59]. Copy number elevation of with addiction and depression [71–73]. COMT is associated with reduced proliferation of neural stem/progenitor cells in  vitro and the migration of their iii. Role of FMR1 in hippocampal neurogenesis and disease progeny in the hippocampus granular layer in  vivo [58] The FMR1 gene encodes the FMRP protein. Results as well as hippocampal volume changes in the CA2/CA3 from many years of research indicate that FMRP acts as regions [59]. The COMT genotype influenced the matu - a transporter carrying mRNA from the nucleus to areas ration of working memory associated with problem solv- of the cell where proteins are assembled [74]. Altered ing and knowledge acquisition skills in both mice and neurogenesis has been reported in an Fmr1-/-knockout humans [40, 41]. mouse model. Animals displayed an increase in neuronal COMT and Wnt signaling are both linked to schizo- differentiation in the DG but no significant difference in phrenia which has been postulated to arise from abnor- the number of neurons added to the DG [12]. The con - mal neurogenesis associated with embryonic neural stem nection between FMR1 and Wnt signaling is supported cells [60–62]. The relationship between COMT and Wnt by the finding that GSK3β, a negative regulator of Wnt signaling in the context of neurogenesis may be based signaling, is elevated in FXS animal models [65]. Cor- on dopamine regulation. The COMT gene has long been rection of the increased GSK3 activity with lithium or considered a candidate gene for schizophrenia because GSK3β inhibitors in mice rescues neurobehavioral and it degrades dopamine and individuals with schizophre- brain morphological abnormalities [75]. Furthermore, nia have increased dopamine levels [63]. Wnt signal- inhibition of GSK3β is reported to improve hippocam- ing is associated with schizophrenia, particularly via the pus-dependent spatial learning tasks and restore neuro- GSK3 gene which acts downstream of the dopamine (D2) genesis in a mouse model of FXS [65]. receptor [64, 65]. Drugs that induce psychosis increase FMRP localizes to axons and dendrites [76]. Studies D2 receptors and drugs that are used to treat psychosis involving both humans and mice support the role of Delprato et al. Behavioral and Brain Functions (2022) 18:7 Page 4 of 11 Network analysis FMRP expression in normal spine morphological devel- The String database (version 11.0) was used to build a opment [77, 78]. The data obtained from human post protein–protein interaction network (PPI) for DCX, mortem tissue derived from donors with FXS and ani- COMT, and FMRP [5, 88]. The network was constructed mal models in which FMRP is underexpressed or not based on experimentally validated interactions using the expressed at all indicate an increase in spine density, medium confidence score of 0.4. The combined scores spine length and immature spine morphology [76, 79]. for the interactions are computed by combining the FMRP has an inhibitory effect on mRNA transla- probabilities from the different evidence channels and tion and regulates translation in pre- and post-synaptic corrected for the probability of randomly observing an terminals [80]. A possible explanation of the effects of interaction. First and 2nd shell interactions are included FMRP in spine dynamics and morphology is by influ- in the network. The network was exported from STRING encing local mRNA translation [81]. A trinucleotide and analyzed in Cytoscape (version 3.7) [6, 89]. Net- repeat mutation in the FMR1 gene is the underly- work clusters and enriched themes were identified with ing cause of FXS [82]. The CGG repeat disrupts gene Cytoscape plugins MCODE (version 1.6.1) and ClueGo expression and as a consequence little or no protein (version 2.5.7) [4, 90]. The nodes in the networks have is produced [82]. FXS is one of the most commonly been manually arranged for proper visibility. inherited forms of ID and monogenic causes of ASD [83, 84]. Results Methods To investigate how these genes may interact we per- Literature review formed a literature review which supported that Wnt The literature review for identifying common themes signaling, neuron migration, and axon and dendrite mor- associated with DCX, COMT, and FMR1 was per- phogenesis were common factors in connecting DCX, formed using PubMed, Google Scholar, and the Online COMT, and FMR1 in ID and social behavior. Based on the Mendelian Inheritance in Man database [85]. Reposi- results of the literature review, we examined RNA-Seq tories and databases were searched using keywords datasets of genes with correlating expression patterns to associations. DCX, COMT, and FMR1 in the developing hippocampus in order to gain further insight. GO annotation was used to identify gene correlates associated with Wnt signal- ing, neurogenesis, social behavior, and ID. Among the Gene sets and evaluation correlates, many genes are linked to Wnt signaling, neu- Microarray data were collected from the Allen Brain rogenesis, and ID and to a lesser extent social behavior Database Developing Human Brain Atlas (https:// (Tables 1, 2, 3, 4). All of the results from the GO analysis human. brain- map. org/, https:// human. brain- map. org/). which includes biological processes, cellular localization, To obtain the data, a gene search for DCX, COMT, molecular function, as well as pathway and disease infor- and FMR1 was performed. Each of these genes were mation are provided in Additional file 2: Workbook S2. used to query the atlas for correlates to the developing The results from the analyses of gene set overlap which hippocampus. was performed to shed light on how these genes might Genes whose expression pattern correlated with DCX, interact at the molecular level, consisted of identifying COMT, and FMR1 were collected for analysis. Correlates common genes among the correlates for DCX, COMT, with a range of Pearson r values from |0.7 to 1.0| were and FMR1. Findings indicate that there were many considered in the analysis (Additional file  1: Workbook shared relevant genes inversely correlated with COMT, S1). The rationale was to investigate genes with a similar DCX, and FMR1 expression patterns particularly in the expression pattern in order to identify correlates specific context of ID (CHAMP1, DCHS1, EML1, MCPH, TCF4, and common to DCX, COMT, and FMR1 associated with CTCF, FAT4, FXR2, GATAD2B, KIAA2022, SETBP1, neurogenesis, Wnt signaling, ID, and social behavior. TAF2, BCAP31, BRWD3, NUFIP1, ATRX) and to a lesser Each gene set was evaluated using Gene Ontology extent social behavior (AUTS2, PCM1). Other shared (GO) enrichment via the Database for Annotation, Visu- correlating genes with relevance are linked to neurogen- alization and Integrated Discovery (DAVID, version 6.8) esis, Wnt signaling, transcription regulation, microtubule [86]. Gene Set overlap among the correlates for DCX, and axon related processes (Table 5 and Additional file  2: COMT, and FMR1 was assessed using Venny 2.0 [87], an Workbook S2). online program that compares lists of items to determine The majority of ID related genes are shared between the shared and unique genes. DCX positive and COMT negative correlates. A possible D elprato et al. Behavioral and Brain Functions (2022) 18:7 Page 5 of 11 Table 1 Wnt pathway genes associated with DCX, COMT and FMR1 correlates in the hippocampus DCX + ACTB, ACTG1, ACVR1B, ARID1A, ARID1B, BCL9, CDH2, CELSR3, CSNK1E, CSNK1G1, CSNK2A1, DACT1, DCHS1, FAT4, FZD7, GNB1, GNG2, HDAC2, MYCN, PCDHB12, PCDHB14, PCDHB2, PCDHB8, PCDHB9, PPP2R5E, PYGO1, SIAH1, SMAD1, SMAD4, SMARCA4, SMARCB1, SMARCD1 DCX − CDH19, DCHS1, GNA14, GNA15, GNG13, GNG7, KREMEN2, MYH13, MYH7B, WNT10A, WNT6, WNT9B COMT + BMPR1B, GNA14, ITPR3, KREMEN2, NFATC1, NFATC2 PPARD, PPP2R5A, SMARCD2, TCF7 COMT − CELSR3, CSNK1G1, CSNK1G3, DACT1, FAT4, GSK3B, HDAC2, MAP3K7, PCDHB3, PPP2R5E, PRKCI FMR1 + LRP6, PPP2CA, PRKCI, SMARCA5, TBL1XR1 FMR1 − DVL1, DVL1P1 Positive and negative associations are indicated with “+” and “−” respectively Table 2 DCX, COMT and FMR1 gene correlates associated with intellectual disability DCX + ACTB, ACTG1, ADNP, ARID1A, ARID1B, AUTS2, BBS9, CASK, CHAMP1, CTCF, DCHS1, DYRK1A, EDC3, EFTUD2, EHMT1, EML1, EXT2, FAT4, FGD1, FOXG1, FRMD4A, FTSJ1, FXR2, GATAD2B, GNB1, IGBP1, KAT6A, KIAA2022, LMAN2L, MCPH1, NONO, OPHN1, POGZ, RBMX, RSPRY1, SETBP1, SMARCA4, SMARCB1, SMC3, SOX11, TAF2, TCF4, TTI2, TUBGCP4, ZC4H2, ZEB2, ZNF711 DCX − BCAP31, MAP2K1 COMT + BCAP31, CHI3L2, CLIC2, HEPACAM, PGAP3, PIGV, PPIC, SLC6A8, TECR, VWA3B COMT − ATP8A2, ATRX, AUTS2, BRWD3, CHAMP1, CTCF, DDX3X, EML1, FAT4, FXR2, GATAD2B, KDM6A, KIAA2022, MCPH1, MED13L, NUFIP1, PAK3, PGAP1, SETBP1, SOX5, TAF2, TCF4, T TC21B, UPF3B FMR1 + AMMECR1, ATRX, BRWD3, COG6, CRBN, CUL4B, FMR1, KIAA0196, KIAA1033, NIPBL, NUFIP1, NUFIP2, RAB3GAP2, RAD21, RBBP8, RPS6KA3, TBL1XR1, TDP2, T TC21B, USP9X, ZDHHC15 FMR1 − No associated genes Positive and negative associations are indicated with “+” and “−” respectively Table 3 DCX, COMT and FMR1 gene correlates associated with Table 4 DCX, COMT and FMR1 neurogenesis related gene social behavior correlates DCX + DNAJC9, AUTS2, EIF4, EBP2 DCX + AKT1, ARID1A, ARID1B, BCL11B, BZW2, CEP120, DACT1, DBN1, DCHS1, DOCK7, DPYSL2, DYNLT1, EFNB2, EPHB1, DCX − SHANK3, ANXA7, MYH14, NPAS4 EPHB2, FAT4, FOXN4, GPSM1, IGSF9, INA, INSM1, ISLR2, COMT + DRD4, UCN KDM1A, KIAA2022, KIDINS220, NEUROD2, NGFR, OPHN1, COMT − KRAS, AUTS2, PCM1 RBM45, SEMA3A, SEMA3C, SEMA4C, SMARCA4, SMARCB1, SMARCD1, SOX11, SRGAP2, STMN1, TCF4, XRCC5 FMR1 + PCM1 DCX − BCL6, CHN1, CIT, GLDN, HAP1, NPAS4, NTRK1, PAX5 FMR1 − DVL1 COMT + BCL6, CSPG5, HAP1, METRN, MT3, NDRG2, PLXNB3, SIRT2, Positive and negative associations are indicated with “ + ” and “-” respectively ZC3H12A COMT − ARHGEF2, BCL11B, BHLHB9, BZW2, CEP120, DACT1, EFNB2, EIF2AK4, EPHA4, EPHA7, FAT4, FBXO45, GSK3B, explanation could be related to the roles of COMT and KIAA2022, KIDINS220, KIF2A, NEUROD6, PCM1, PRDM8, ROBO2, SEMA3A, SEMA3C, SPAST, STMN1, TCF4, XRCC5 DCX and their effects on brain structure and neurogene - FMR1 + CCDC88A, EIF2AK4, HOOK3, IMPACT, PCM1, PHF10 sis. In patients with schizophrenia the COMT Val allele is SETX, ZEB1 associated with smaller temporal and frontal brain areas FMR1 − RFNG [91] and as described in the Introduction, DCX variants Positive and negative associations are indicated with “+” and “−” respectively cause severe lamination defects in the cortical and hip- pocampus regions [92]. In addition, there is supporting evidence that increased dopamine neurotransmission interactions for DCX, COMT, and FMRP was per- stimulates neurogenesis [93, 94]. formed. An assessment of network topology and con- The shared genes between COMT and FMR1 are also nectivity indicates that the individual PPI networks for inversely correlated and are associated with similar rel- these genes connect (Fig. 1, Additional file  3: Workbook evant themes (Table  5). There were no relevant genes S3). common between FMR1 and DCX. The DCX and FMRP networks are more highly inter - To gain further insight, an analysis of protein–pro- connected via proteins associated with RNA binding tein interaction networks of experimentally validated and cell cycle such as FXR1/2 and CYFIP2, whereas the Delprato et al. Behavioral and Brain Functions (2022) 18:7 Page 6 of 11 Table 5 Relevant shared gene correlates for DCX, COMT and FMR1 COMT +/DCX − BCAP31 Apoptosis, ubiquitin dependent catabolic process protein transport, X-linked mental retardation, dystonia, cerebral hypomyelination BCL11B Neurogenesis, axon guidance, neuron projection, transcription, splicing, methylation GNA14 Signal transduction phospholipase C-activating dopamine receptor signaling pathway HAP1 Synaptic transmission axonal transport, cerebellum development, cell projection organization, neurogenesis, transport along micro- tubules KREMEN2 Wnt signalling COMT −/DCX + AUTS2 Transcription regulation, Autism, mental retardation/ID BZW2 Nervous system development, cell–cell adhesion, neurogenesis CELSR3 Neuron migration, axonal fasciculation, dopaminergic serotonergic neuron axon guidance, Wnt signaling pathway CEP120 Regulation of centrosome duplication, cerebral cortex development, neurogenesis, astral microtubule organization CHAMP1 Protein localization to kinetochore, protein localization to microtubule, attachment of mitotic spindle microtubules to kinetochore CSNK1G1 Endocytosis, regulation of cell shape, Wnt and Hedgehog signaling CTCF Transcription regulation, DNA methylation, mental retardation, Mental retardation, autosomal dominant 21 DACT1 Transcription regulation, Wnt signaling EFNB2 Cell adhesion, axon guidance, neurogenesis EML1 Microtubule cytoskeleton organization, epilepsy, mental retardation FAT4 Neurogenesis, cerebral cortex development, cell adhesion, mental retardation/ID FXR2 RNA transport, negative regulation of translation, Fragile X mental retardation GATAD2B Transcription, DNA methylation, mental retardation/ID HDAC2 Transcription regulation, chromatin remodeling neuron projection and dendrite development KIAA2022 Nervous system development, X-linked mental retardation, neurogenesis mental retardation, X-linked 98, neurite extension and migration KIDINS220 Dendrite morphogenesis, neuron projection development, neurogenesis MCPH1 Mitotic spindle orientation, regulation of gene expression, cerebral cortex development, mental retardation, Microcephaly 1, pri- mary, autosomal recessive SEMA3A Neuron migration, axon guidance, neurogenesis SEMA3C Neuron migration, axon guidance, neurogenesis SETBP1 DNA binding, Schinzel-Giedion midface retraction syndrome, mental retardation, autosomal dominant 29 STMN1 Microtubule depolymerization, mitotic spindle organization, axongenesis, neurogenesis TAF2 Transcription regulation, mental retardation/ID Mental retardation, autosomal recessive 40 TCF4 Transcription regulation, neurogenesis, epilepsy, mental retardation, Pitt-Hopkins syndrome XRCC5 Transcription, DNA recombination, neurogenesis FMR1 +/COMT − ATRX DNA methylation, chromatin remodeling, transcription, Mental retardation: alpha-thalassemia/mental retardation syndrome, mental retardation-hypotonic facies syndrome, X-linked 52/intellectual development disorder BRWD3 Transcription regulation, mental retardation X-linked intellectual developmental disorder EIF2AK4 Translation, ribosome structure and biogenesis, learning and long-term memory NUFIP1 RNA processing, transcription fragile X mental retardation-interacting protein 1 PCM1 Neuron migration, microtubule organization and anchoring, social behavior, negative regulation of neurogenesis T TC21B Transcription regulator, smoothened signaling pathway regulation FMR1 −/COMT + GAS6 Dendritic cell differentiation, apoptosis KIF19 Axon, microtubule depolymeriation NDUFS7 Synapse, neuron projection Positive and negative correlative gene expression patterns are indicated with “+” and “−” respectively D elprato et al. Behavioral and Brain Functions (2022) 18:7 Page 7 of 11 Fig. 1 DCX, COMT, and FMRP PPI network. A topological evaluation of PPI networks of DCX, COMT, and FMRP indicates that DCX and FMRP networks are highly interconnected, whereas the COMT network is peripherally associated with the DCX network through second shell interactions. Red lines represent first shell interactions which are proteins directly associated with DCX, COMT, and FMRP. Gray lines indicate second shell interactions which are proteins linked with the other proteins in the first shell i.e., not DCX, COMT, or FMR1P COMT network is linked to the DCX and FMRP net- well as several other relevant classifications (Fig.  2 and works via the neurotrophic factor S100B which enhances Additional file 4: Workbook S4). hippocampal neurogenesis in rodent models, as well as the microtubule associated proteins MAPT, which pro- Conclusions motes microtubule assembly and stability and TUBA1A Polymorphisms in the DCX, COMT, and FMR1 genes which is a fundamental component of microtubules are associated with severe and diverse brain develop- [95–98]. ment and neuropsychiatric disorders. Each of these Assignment of over-represented themes based on GO genes has been linked to ID and social behavior. To and pathway analysis of the PPI network modules are: investigate how these genes may interact we performed Module 1. RNA process translation initiation elongation, a literature review which pointed to Wnt signaling, Module 2. Microtubule tubulin cytoskeleton cell cycle, neuron migration, and axon and dendrite morphogen- Module 3. Mitogenic cell survival embryonic develop- esis as common factors. ment cell growth morphogenesis tissue repair, Module Based on the results from the literature review, we 4. Anaphase cell cycle mitotic, cell division and ubiq- analyzed gene expression patterns in the developing uitin processes, Module 5. Actin polymerization cell hippocampus to gain additional support and insight migration, Module 6. Nuclear transport, RNA processes into the relationship between these genes in the con- (Fig. 1). text of identifying molecular interactions and signaling An analysis of neurogenesis related genes from the pathways that may connect them. The findings from DCX, COMT, and FMR1 correlates in the context of these analyses support the results obtained from the enriched functional categories results in thirty-two literature review and provide useful information for fol- groups and within those groups one hundred and ninety- low up studies. one GO annotations. Among the categories there are many related to axon, dendrite, and neuron processes as Delprato et al. Behavioral and Brain Functions (2022) 18:7 Page 8 of 11 Fig. 2 Functional enrichment of DCX, COMT, and FMRP correlates linked to neurogenesis Neurogenesis related gene correlates were further evaluated for functional associations in the context of biological process and pathway integration. Enriched themes include axon guidance, axiogenesis, cell projection and dendritic processes. Red stars indicate functional enrichment themes with particular relevance to the study. Colors are chosen arbitrarily for distinction and to depict overlap. Availability of data and materials Supplementary Information All data are provided with the manuscript. The online version contains supplementary material available at https:// doi. org/ 10. 1186/ s12993- 022- 00191-7. Declarations Additional file 1: Workbook S1. DCX, COMT , and FMR1 hippocampal Ethics approval and consent to participate gene correlates. Not applicable. Additional file 2: Workbook S2. Gene Ontology analysis of DCX, COMT , and FMR1 hippocampal gene correlates. Consent for publication Additional file 3: Workbook S3. DCX, COMT, and FMRP protein–protein Not applicable. interaction network. Competing interests Additional file 4: Workbook S4. DCX, COMT , and FMR1 functional enrich- Not applicable. ment categories for neurogenesis genes. Author details Department of Research and Education, BioScience Project, Wakefield, MA Acknowledgements 01880, USA. Alexander Mackenzie High School, Richmond Hill, ON 14519, Not applicable. Canada. Lambert High School, Suwanee, GA 30024, USA. Authors’ contributions Received: 4 June 2021 Accepted: 14 March 2022 All authors conducted the study, analyzed the data, and wrote and reviewed the manuscript. AD designed and supervised the study. EX and DM con- tributed equally to this study. All the authors read and approved the final manuscript. References Funding 1. Kwan V, Unda BK, Singh KK. Wnt signaling networks in autism spectrum This work was supported by the BioScience Project Research and Education disorder and intellectual disability. J Neurodev Disord. 2016;5(8):45. Organization. 2. Jones AR, Overly CC, Sunkin SM. The Allen Brain Atlas: 5 years and beyond. Nat Rev Neurosci. 2009;10(11):821–8. D elprato et al. Behavioral and Brain Functions (2022) 18:7 Page 9 of 11 3. Conway JR, Lex A, Gehlenborg N. UpSetR: an R package for the intellectual disability with gender-specific effects on Wnt signaling. Am J visualization of intersecting sets and their properties. Bioinformatics. 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Journal

Behavioral and Brain Functions – Springer Journals

Published: May 19, 2022

Keywords: Intellectual disability; Social behavior; Neurogenesis; Hippocampus; Wnt signaling; COMT; DCX; FMR1

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