Genetic and functional analysis reveals TENM4 contributes to schizophrenia

Yi, Xin; Li, Minzhe; He, Guang; Du, Huihui; Li, Xingwang; Cao, Dongmei; Wang, Lu; Wu, Xi; Yang, Fengping; Chen, Xu; Ping, Yong; Zhou, Daizhan

doi:10.1016/j.isci.2021.103063

Cited by 16 publications

(7 citation statements)

References 74 publications

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“…For example, in WT but not Csf1r null mice exposed to MIA, migrating neurons showed increased expression of Flrt1 , which encodes a cell-cell adhesion molecule that regulates neuronal migration and neurite outgrowth 35,36 . Migrating neurons, corticothalamic projection neurons (CThPNs), and callosal projection neurons (CPNs) showed increased expression of Tenm4 , a risk gene for schizophrenia that encodes a transmembrane protein that regulates axon guidance 37,38 . APs showed increased expression of Auts2 , a marker of frontal cortical identity that is involved in synapse formation and axon elongation 39 .…”

Section: Resultsmentioning

confidence: 99%

Fetal brain response to maternal inflammation requires microglia

Elaine LaMonica Ostrem,

Dominguez Iturza,

Stogsdill

et al. 2024

Preprint

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In uteroinfection and maternal inflammation can adversely impact fetal brain development. Maternal systemic illness, even in the absence of direct fetal central nervous system infection, is associated with an increased risk of autism and schizophrenia in affected offspring. The cell types mediating the response of the fetal brain to maternal inflammation are largely unknown, hindering the development of therapies to prevent and treat adverse neuropsychiatric outcomes. Here, we show that microglia, the resident phagocytes of the brain, are enriched for expression of receptors for relevant pathogens and cytokines, throughout embryonic development. Using a rodent maternal immune activation (MIA) model in which polyinosinic:polycytidylic acid is injected into pregnant dams, we demonstrate long-lasting transcriptional changes in fetal microglia that persist into postnatal life. We find that MIA induces widespread gene expression changes in neuronal and non-neuronal cells; importantly, these responses are abolished by selective genetic deletion of microglia, indicating that microglia are required for the transcriptional response of other cortical cell types to MIA. These findings demonstrate that microglia play a critical, durable role in fetal response to maternal inflammation, pointing at microglia as a potential therapeutic cell target.

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Section: Resultsmentioning

confidence: 99%

Fetal brain response to maternal inflammation requires microglia

Elaine LaMonica Ostrem,

Dominguez Iturza,

Stogsdill

et al. 2024

Preprint

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“…TENM3 knockout mice were delayed in developing motor skills (Tran et al, 2015). Teneurins are genetically associated with bipolar disorder and schizophrenia (Yi et al, 2021). TENM3 is associated with childhood autoimmune diseases (Li et al, 2015), and the presence of autoantibodies to N-methyl-d-aspartate-receptor subunit-NR1 (NMDAR1), the most common antigen for anti-brain autoantibodies (Daguano Gastaldi et al, 2023).…”

Section: Discussionmentioning

confidence: 99%

Common and rare variant analyses implicate late-infancy cerebellar development and immune genes in ADHD

Zhong,

Baum,

Tubbs

et al. 2023

Preprint

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BackgroundAttention-deficit hyperactivity disorder (ADHD) is a common neuropsychiatric disorder with a significant genetic component, characterized by persistent symptoms of inattention, hyperactivity, and/or impulsivity. The latest genome-wide association study (GWAS) meta-analysis of ADHD identified 27 whole-genome significant risk loci in the European population. However, genetic risk factors for ADHD are less well-characterized in the Asian population, especially for rare variants.MethodsHere, we present an analysis of common and rare variant contributions to ADHD in a Hong Kong sample comprising 279 cases and 432 controls, who were genotyped using the Illumina Infinium Global Screening Array.ResultsWe identified 41 potential genomic risk loci with a suggestive association (p< 1e−4), pointing to 111 candidate risk genes, which were enriched for genes differentially expressed during late infancy brain development. Furthermore, tissue enrichment analysis implicated the involvement of the cerebellum.POC1B, a gene previously found in a genome-wide significant locus of ADHD in the European population, was replicated in the current study, potentially implicating a trans-ancestral effect in ADHD. In addition, an accumulation of ADHD common-variant risks found in European ancestry samples was found to be significantly associated with ADHD in the current study. At the polygenic level, we also discovered a strong genetic correlation with resting-state functional MRI connectivity of the cerebellum involved in the attention/central executive and subcortical-cerebellum networks, which is consistent with the neural pathophysiology for ADHD. In rare variant analyses, we discovered that ADHD cases carried an elevated load of rare damaging variants inTEP1,MTMR10,DBH,TBCC,andANO1. ADHD genetic risk was associated with immune processes, demonstrated in both common and rare variant analyses.ConclusionsThese findings re-validate the abnormal development of the neural system in ADHD and extend the existing neuro-dysfunction hypothesis to a multi-system perspective.

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“…Teneurins also regulate diverse other biological processes including cell polarity, neuronal migration, axon guidance and target selection, axon myelination, and synapse development [6][7][8][9][10][11][12][13][14][15][16][17] . All four human teneurins have been implicated in a variety of diseases including sensory dysfunctions, movement disorders, neurodevelopmental and psychiatric disorders, and cancers [18][19][20][21][22][23][24][25][26] .…”

Section: Introductionmentioning

confidence: 99%

Molecular and Cellular Mechanisms of Teneurin Signaling in Synaptic Partner Matching

Xu,

Li,

Lyu

et al. 2024

Preprint

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SUMMARYIn developing brains, axons exhibit remarkable precision in selecting synaptic partners among many non-partner cells. Evolutionally conserved teneurins were the first identified transmembrane proteins that instruct synaptic partner matching. However, how intracellular signaling pathways execute teneurin’s functions is unclear. Here, we usein situproximity labeling to obtain the intracellular interactome of teneurin (Ten-m) in theDrosophilabrain. Genetic interaction studies using quantitative partner matching assays in both olfactory receptor neurons (ORNs) and projection neurons (PNs) reveal a common pathway: Ten-m binds to and negatively regulates a RhoGAP, thus activating the Rac1 small GTPases to promote synaptic partner matching. Developmental analyses with single-axon resolution identify the cellular mechanism of synaptic partner matching: Ten-m signaling promotes local F-actin levels and stabilizes ORN axon branches that contact partner PN dendrites. Combining spatial proteomics and high-resolution phenotypic analyses, this study advanced our understanding of both cellular and molecular mechanisms of synaptic partner matching.HIGHLIGHTSIn situspatial proteomics reveal the first intracellular interactome of teneurinsTen-m signals via a RhoGAP and Rac1 GTPase to regulate synaptic partner matchingSingle-axon analyses reveal a stabilization-upon-contact model for partner matchingTen-m signaling promotes F-actin in axon branches contacting partner dendrites

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Genetic and functional analysis reveals TENM4 contributes to schizophrenia

Abstract: HighlightsPossible pathogenic rare missense mutations in TENM4 gene contribute to SCZ Aberrant expression of Ten-m leads to behavioral disturbances related to SCZ symptomsTen-m affects stimulation, metabolic process, neurogenesis, and ATPase activity

Cited by 16 publications

References 74 publications

Fetal brain response to maternal inflammation requires microglia

Fetal brain response to maternal inflammation requires microglia

Common and rare variant analyses implicate late-infancy cerebellar development and immune genes in ADHD

Molecular and Cellular Mechanisms of Teneurin Signaling in Synaptic Partner Matching

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