Formin1 Mediates the Induction of Dendritogenesis and Synaptogenesis by Neurogenin3 in Mouse Hippocampal Neurons

Simon-Areces, Julia; Dopazo, Ana; Dettenhofer, Markus; Rodríguez‐Tébar, Alfredo; Garcia-Segura, Luis Miguel; Arévalo, María Ángeles

doi:10.1371/journal.pone.0021825

Cited by 27 publications

(15 citation statements)

References 45 publications

(47 reference statements)

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“… FMN1 protein and calcium-activated ANO2 chloride channels are expressed in the dendritic spines of excitatory synapses [ 22 , 23 ], whereas GAD67 (the enzyme produced by the GAD1 gene) is expressed in the axonal termini of inhibitory GABAergic interneurons. It has been shown that impairment of these genes induces: dendritic arborization abnormalities ( FMN1 ) [ 23 ], alterations in action potential duration and in the threshold for action potential generation ( ANO2 ) [ 22 ], and the dysfunctional synthesis of the GABA neurotransmitter ( GAD1 ) [ 24 ]. At different levels, the impairment of these genes might affect the complex excitatory/inhibitory balance across cortical circuits that is believed to be altered in schizophrenic patients [ 25 ].…”

Section: Discussionmentioning

confidence: 99%

Exome sequencing in schizophrenic patients with high levels of homozygosity identifies novel and extremely rare mutations in the GABA/glutamatergic pathways

et al. 2017

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Inbreeding is a known risk factor for recessive Mendelian diseases and previous studies have suggested that it could also play a role in complex disorders, such as psychiatric diseases. Recent inbreeding results in the presence of long runs of homozygosity (ROHs) along the genome, which are also defined as autozygosity regions. Genetic variants in these regions have two alleles that are identical by descent, thus increasing the odds of bearing rare recessive deleterious mutations due to a homozygous state. A recent study showed a suggestive enrichment of long ROHs in schizophrenic patients, suggesting that recent inbreeding could play a role in the disease. To better understand the impact of autozygosity on schizophrenia risk, we selected, from a cohort of 180 Italian patients, seven subjects with extremely high numbers of large ROHs that were likely due to recent inbreeding and characterized the mutational landscape within their ROHs using Whole Exome Sequencing and, gene set enrichment analysis. We identified a significant overlap (17%; empirical p-value = 0.0171) between genes inside ROHs affected by low frequency functional homozygous variants (107 genes) and the group of most promising candidate genes mutated in schizophrenia. Moreover, in four patients, we identified novel and extremely rare damaging mutations in the genes involved in neurodevelopment (MEGF8) and in GABA/glutamatergic synaptic transmission (GAD1, FMN1, ANO2). These results provide insights into the contribution of rare recessive mutations and inbreeding as risk factors for schizophrenia. ROHs that are likely due to recent inbreeding harbor a combination of predisposing low-frequency variants and extremely rare variants that have a high impact on pivotal biological pathways implicated in the disease. In addition, this study confirms that focusing on patients with high levels of homozygosity could be a useful prioritization strategy for discovering new high-impact mutations in genetically complex disorders.

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Section: Discussionmentioning

confidence: 99%

Exome sequencing in schizophrenic patients with high levels of homozygosity identifies novel and extremely rare mutations in the GABA/glutamatergic pathways

et al. 2017

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“…Among the genes affecting microtubule dynamics we found one that is associated to a cellular phenotype in the same tissue where the human eQTL is affecting expression levels: FMN1 in the hippocampus. Overexpression of FMN1 promotes primary dendritic development in the hippocampus [Simon-Areces et al, 2011]. Whether FMN1 overexpression would have the same effect in human hippocampus is currently unknown, but this example shows how the present study can open new testable hypotheses for human evolution studies concerning understudied subcortical structures.…”

Section: Discussionmentioning

confidence: 77%

Modern human alleles differentially regulate gene expression across brain regions: implications for brain evolution

Andirkó

Boeckx

2019

Preprint

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8The high-quality sequence of the genomes of our extinct relatives, Ne-9 anderthals and Denisovans, became recently public. At the same time, 10 we have seen the emergence of big databases of modern human genetic 11 variation. However, linking human genetic variation, neuronal phenotypes 12 and, eventually, behaviour, is only possible if we understand how variation 13 and genetic regulation interact. We used two publicly available datasets, 14 the GTEX cis-eQTL database (v7) and a catalog of high-frequency Homo 15 Sapiens specific alleles relative to the Neanderthals and Denisovan se-16 quences, to understand how high-frequency Homo Sapiens derived alleles 17 affect gene expression regulation. The resulting dataset shows that genes 18 associated with brain development are affected by Homo sapiens-specific 19 eQTL in brain areas key in human evolution such as the cerebellum. We 20 also show that some of these eQTL overlap significantly with putative 21 regions of positive selection relative to archaic humans [Peyrégne et al., 22 2017]. Additionally, we tested whether any of the variants are associated 23 with clinical conditions in modern human populations. These findings can 24 inform future experimental work and enrich current venues of research of 25 the Homo Sapiens brain evolution, such as the relationship between clini-26 cal and evolutionary research and the recent expansion of the cerebellum 27 in Homo Sapiens [Gunz et al., 2010].28 Keywords-Human evolution, eQTL, brain evolution 29 and Boeckx, 2019]). 75 Our results show differential regulation by derived cis-eQTLs in key brain 76 areas and circuits that are claimed to have changed significantly during the 77 emergence of Homo sapiens, such as the cerebellum and olfactory signalling 78 pathway [Bastir et al., 2011]. We also found genetic regulation of cellular pro-79 cesses that can potentially impact neurodevelopment and disease, such as fo-80 late one-carbon metabolism, aerobic glycolysis regulation, cell-cell adhesion and 81 regulation of cytoskeleton dynamics. Some of these processes, such as aerobic 82 glycolysis, have already been discussed in other studies in the context of human 83 evolution and human-specific diseases such as Alzheimer's Disease [Bufill et al., 84 2011]. While we limited the scope of our study to brain tissue, we found as 85 well eQTLs associated with neural crest cell development and the craniofacial 86 complex. This is of special interest, as the Homo sapiens face has a distinct re-87 tracted profile compared to that of archaic humans [Lacruz et al., 2019]. Some 88 of the genes that affect brain development might exert an influence in adjacent 89 tissues [Boeckx, 2017]. 90 Since the eQTLs affect genes previously identified as under selective sweep in 91 modern humans relative to archaic humans, we tested whether the eQTLs affect 92 128 2015]. In this case, the effect of an eQTL is understood as the relative gene 129 expression difference between the minor, ancestral allele and the high-frequency 130 derived allele. As shown ...

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“…This CNV encompasses two exons of the FMN1 gene, which encodes the protein Formin1. The overexpression of Formin1b produces an increase in the number of primary dendrites in cultured hippocampal neurons and an increase in the number of glutamatergic synaptic inputs [27] . Additionally, it is thought that Formin1 may mediate the effect of the proneural transcription factor Ngn3, which regulates dendritogenesis and synaptogenesis [28] .…”

Section: Discussionmentioning

confidence: 99%

An Inherited Small Microdeletion at 15q13.3 in a Patient with Early- Onset Obsessive-Compulsive Disorder

Cappi

Hounie

Mariani³

et al. 2014

PLoS ONE

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Copy number variations (CNVs) have been previously associated with several different neurodevelopmental psychiatric disorders, such as autism, schizophrenia, and attention deficit hyperactivity disorder (ADHD). The present study consisted of a pilot genome-wide screen for CNVs in a cohort of 16 patients with early-onset obsessive-compulsive disorder (OCD) and 12 mentally healthy individuals, using array-based comparative genomic hybridization (aCGH) on 44K arrays. A small rare paternal inherited microdeletion (∼64 kb) was identified in chromosome 15q13.3 of one male patient with very early onset OCD. The father did not have OCD. The deletion encompassed part of the FMN1 gene, which is involved with the glutamatergic system. This finding supports the hypothesis of a complex network of several genes expressed in the brain contributing for the genetic risk of OCD, and also supports the glutamatergic involvement in OCD, which has been previously reported in the literature.

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Formin1 Mediates the Induction of Dendritogenesis and Synaptogenesis by Neurogenin3 in Mouse Hippocampal Neurons

Cited by 27 publications

References 45 publications

Exome sequencing in schizophrenic patients with high levels of homozygosity identifies novel and extremely rare mutations in the GABA/glutamatergic pathways

Exome sequencing in schizophrenic patients with high levels of homozygosity identifies novel and extremely rare mutations in the GABA/glutamatergic pathways

Modern human alleles differentially regulate gene expression across brain regions: implications for brain evolution

An Inherited Small Microdeletion at 15q13.3 in a Patient with Early- Onset Obsessive-Compulsive Disorder

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