Serotonin abnormalities in Engrailed-2 knockout mice: New insight relevant for a model of Autism Spectrum Disorder

Viaggi, Cristina; Gerace, Claudio; Pardini, Carla; Corsini, Giovanni; Vaglini, Francesca

doi:10.1016/j.neuint.2015.05.004

Cited by 16 publications

(15 citation statements)

References 37 publications

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“…Moreover, axonal guidance in target territories to establish adequate synaptic patterning depend of engrailed proteins concentration ( Marie and Blagburn, 2003 ); then, decreasing of EN2 transcription could represent a haploinsufficient phenotype that predispose to MR and ASD in 7q terminal deletion syndrome. Moreover, recent findings En2 knockout mice display reduced levels of tyrosine hydroxylase, noradrenaline, and serotonin in the hippocampus and cerebral cortex, similar to those observed in human brains with ASD ( Viaggi et al, 2015 ). In addition, Soltani et al (2017) , have reported an effect of En2 protein in neuronal morphogenesis and synaptogenesis of hippocampal neurons in culture.…”

Section: Discussionsupporting

confidence: 68%

“…ASD is a neurodevelopmental disorder with a strong genetic component. A close relationship between ASD and EN2 specific polymorphisms, as well as genetic and epigenetic alterations, has been established in several studies, suggesting that the etiologic influence of EN2 variants in ASD may be explained through genetic mechanisms ( Petit et al, 1995 ; Blair et al, 2002 ; Brune et al, 2008 ; Benayed et al, 2009 ; Sen et al, 2010 ; Viaggi et al, 2015 ). Although the underlying genetic architecture is not well understood, two theories explain the genetic roots of common complex diseases, including the ASD.…”

Section: Discussionmentioning

confidence: 95%

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Clinical Phenotypes Associated to Engrailed 2 Gene Alterations in a Series of Neuropediatric Patients

et al. 2018

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The engrailed homeobox protein (EN) plays an important role in the regionalization of the neural tube. EN distribution regulates the cerebellum and midbrain morphogenesis, as well as retinotectal synaptogenesis. In humans, the EN1 and EN2 genes code for the EN family of transcription factors. Genetic alterations in the expression of EN2 have been related to different neurologic conditions and more particularly to autism spectrum disorders (ASD). We aimed to study and compare the phenotypes of three series of patients: (1) patients with encephalic structural anomalies (ESA) and abnormalities in the genomic (DNA) and/or transcriptomic (RNAm) of EN2 (EN2-g), (2) ESA patients having other gene mutations (OG-g), and (3) ESA patients free of these mutations (NM-g).Subjects and Methods: We have performed a descriptive study on 109 patients who suffer from mental retardation (MR), cerebral palsy (CP), epilepsy (EP), and behavioral disorders (BD), showing also ESA in their encephalic MRI. We studied genomic DNA and transcriptional analysis (cDNA) on EN2 gene (EN2), and in other genes (OG): LIS1, PTAFR, PAFAH1B2, PAFAH1B3, FGF8, PAX2, D17S379, D17S1866, and SMG6 (D17S5), as a routine genetic diagnosis in ESA patients.Results: From 109 patients, fifteen meet the exclusion criteria. From the remaining 94 patients, 12 (12.8%) showed mutations in EN2 (EN2-g), 20 showed mutations in other studied genes (OG-g), and 62 did not showed any mutation (NM-g). All EN2-g patients, suffered from MR, nine EP, seven BD and four CP. The proportions of these phenotypes in EN2-g did not differ from those in the OG-g, but it was significantly higher when comparing EN2-g with NM-g (MR: p = 0.013; EP: p = 0.001; BD: p = 0.0001; CP: p = 0.07, ns). Groups EN2-g and OG-g showed a 100 and a 70% of comorbidity, respectively, being significantly (p = 0.04) greater than NM-group (62.9%).Conclusion: Our series reflects a significant effect of EN2 gene alterations in neurodevelopmental abnormalities associated to ESA. Conversely, although these EN2 related anomalies might represent a predisposition to develop brain diseases, our results did not support direct relationship between EN2 mutations and specific clinical phenotypes.

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Section: Discussionsupporting

confidence: 68%

Section: Discussionmentioning

confidence: 95%

Clinical Phenotypes Associated to Engrailed 2 Gene Alterations in a Series of Neuropediatric Patients

et al. 2018

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“…Mice lacking the homeobox domain of En2 ( En2 hd / hd mice; Joyner et al, 1991; here referred to as En2 −/− ) display neuropathological changes related to ASD. These defects include cerebellar hypoplasia and reduced number of Purkinje neurons (Joyner et al, 1991; Kuemerle et al, 1997), defective GABAergic innervation in the forebrain (Sgadò et al, 2013a; Allegra et al, 2014; Provenzano et al, 2014), reduced monoaminergic innervation to the forebrain (Brielmaier et al, 2014; Genestine et al, 2015; Viaggi et al, 2015) and ASD-like behavioral traits such as decreased sociability, spatial learning deficits, and increased seizure susceptibility (Cheh et al, 2006; Tripathi et al, 2009; Brielmaier et al, 2012; Provenzano et al, 2014). …”

Section: Introductionmentioning

confidence: 99%

Comparative Gene Expression Analysis of Two Mouse Models of Autism: Transcriptome Profiling of the BTBR and En2−/− Hippocampus

et al. 2016

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Autism spectrum disorders (ASD) are characterized by a high degree of genetic heterogeneity. Genomic studies identified common pathological processes underlying the heterogeneous clinical manifestations of ASD, and transcriptome analyses revealed that gene networks involved in synapse development, neuronal activity, and immune function are deregulated in ASD. Mouse models provide unique tools to investigate the neurobiological basis of ASD; however, a comprehensive approach to identify transcriptional abnormalities in different ASD models has never been performed. Here we used two well-recognized ASD mouse models, BTBR T+ Itpr3tf/J (BTBR) and Engrailed-2 knockout (En2−/−), to identify conserved ASD-related molecular signatures. En2−/− mice bear a mutation within the EN2 transcription factor homeobox, while BTBR is an inbred strain with unknown genetic defects. Hippocampal RNA samples from BTBR, En2−/− and respective control (C57Bl/6J and En2+/+) adult mice were assessed for differential gene expression using microarrays. A total of 153 genes were similarly deregulated in the BTBR and En2−/− hippocampus. Mouse phenotype and gene ontology enrichment analyses were performed on BTBR and En2−/− hippocampal differentially expressed genes (DEGs). Pathways represented in both BTBR and En2−/− hippocampal DEGs included abnormal behavioral response and chemokine/MAP kinase signaling. Genes involved in abnormal function of the immune system and abnormal synaptic transmission/seizures were significantly represented among BTBR and En2−/− DEGs, respectively. Interestingly, both BTBR and En2−/− hippocampal DEGs showed a significant enrichment of ASD and schizophrenia (SCZ)-associated genes. Specific gene sets were enriched in the two models: microglial genes were significantly enriched among BTBR DEGs, whereas GABAergic/glutamatergic postsynaptic genes, FMRP-interacting genes and epilepsy-related genes were significantly enriched among En2−/− DEGs. Weighted correlation network analysis (WGCNA) performed on BTBR and En2−/− hippocampal transcriptomes together identified six modules significantly enriched in ASD-related genes. Each of these modules showed a specific enrichment profile in neuronal and glial genes, as well as in genes associated to ASD comorbidities such as epilepsy and SCZ. Our data reveal significant transcriptional similarities and differences between the BTBR and En2−/− hippocampus, indicating that transcriptome analysis of ASD mouse models may contribute to identify novel molecular targets for pharmacological studies.

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“…En2 knockout mice (En2-/-) display subtle cerebellar neuropathological chang-es and reduced levels of tyrosine hydroxylase, noradrenaline, and serotonin in the hippocampus and cerebral cortex similar to those ones which have been observed in the ASD brain [170]. The disruption of hindbrain patterning genes can alter monoamine system development and thereby produce forebrain defects that are relevant to human neurodevelopmental disorders [171].…”

Section: Mendelian Asd Disorders In Dna Methylation Machinerymentioning

confidence: 99%

The Genetic and Epigenetic Basis Involved in the Pathophysiology of ASD: Therapeutic Implications

Carrascosa-Romero¹,

Cabo²

2017

Autism - Paradigms, Recent Research and Clinical Applications

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The prevalence of autism has increased in an exponential way in the past few years. Many monogenetic mutations as well as copy number variants and single nucleotide polymorphisms have been associated with autism spectrum disorders (ASD), a large proportion of which occur in genes associated with synaptogenesis and synaptic function. However, the increase in appearance of genetic alterations does not explain the etiology of an elevated number of ASD cases. Recent research is now focusing on the role of environmental/epigenetic factors, which by themselves and/or in combination with classical genetic factors, may be the root cause of a large number of ASDs. In this chapter we review the current literature regarding the epigenetic changes involved in ASD, including their possible mechanisms of action such as oxidative stress, altered fatty acid metabolism, mitochondrial dysfunction, DNA methylation and histone methylation (via the one-carbon metabolism cycle), histone variants, and ATP-dependent chromatin remodeling. We discuss possible new biochemical markers related to autism as well as new lines of research for therapeutic targets.

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Serotonin abnormalities in Engrailed-2 knockout mice: New insight relevant for a model of Autism Spectrum Disorder

Cited by 16 publications

References 37 publications

Clinical Phenotypes Associated to Engrailed 2 Gene Alterations in a Series of Neuropediatric Patients

Clinical Phenotypes Associated to Engrailed 2 Gene Alterations in a Series of Neuropediatric Patients

Comparative Gene Expression Analysis of Two Mouse Models of Autism: Transcriptome Profiling of the BTBR and En2−/− Hippocampus

The Genetic and Epigenetic Basis Involved in the Pathophysiology of ASD: Therapeutic Implications

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