Partial Deletion of Chromosome 1p31.1 Including only the Neuronal Growth Regulator 1 Gene in Two Siblings

Genovese, Ann; Cox, Devin M.; Butler, Merlin G.

doi:10.1055/s-0035-1554977

Cited by 19 publications

(12 citation statements)

References 14 publications

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“…For example, gene variants of SynCAMs, which possess three extracellular Ig-like domains as IgLON proteins, have been identified as causal or risk factors for intellectual disability and autism spectrum disorders and SynCAM-deficient mice exhibit social and emotional deficits (Frei and Stoeckli, 2017 ; Gennarini and Furley, 2017 ). More recently, genetic variants in or near the NEGR1 locus have been associated with cognitive disorders including psychiatric disease, intellectual disability and learning difficulties (Veerappa et al, 2013 ; Genovese et al, 2015 ; Tassano et al, 2015 ; Hyde et al, 2016 ). These findings prompted us to examine the brain distribution of NEGR1 mRNA, its role in neurite and axon growth and to provide an initial neuroanatomical and behavioral characterization of Negr1 -KO mice.…”

Section: Discussionmentioning

confidence: 99%

“…Gene variants in a regulatory region upstream of the NEGR1 gene have been associated with major depressive disorder (Hyde et al, 2016 ) but also with low white matter integrity (Dennis et al, 2014 ) and intelligence (Sniekers et al, 2017 ). Neuropsychiatric problems and learning difficulties were further reported in two siblings with a mono-allelic microdeletion of chromosome 1p31.1 involving only the NEGR1 gene (Genovese et al, 2015 ). Interestingly, increased cerebrospinal fluid protein levels of NEGR1 were found in major depressive disorder and bipolar disease but not schizophrenia compared to controls (Maccarrone et al, 2013 ).…”

Section: Introductionmentioning

confidence: 99%

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Neuronal Growth and Behavioral Alterations in Mice Deficient for the Psychiatric Disease-Associated Negr1 Gene

Singh

Loreth

Pöttker

et al. 2018

Front. Mol. Neurosci.

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Neuronal growth regulator 1 (NEGR1), a member of the immunoglobulin superfamily cell adhesion molecule subgroup IgLON, has been implicated in neuronal growth and connectivity. In addition, genetic variants in or near the NEGR1 locus have been associated with obesity and more recently with learning difficulties, intellectual disability and psychiatric disorders. However, experimental evidence is lacking to support a possible link between NEGR1, neuronal growth and behavioral abnormalities. Initial expression analysis of NEGR1 mRNA in C57Bl/6 wildtype (WT) mice by in situ hybridization demonstrated marked expression in the entorhinal cortex (EC) and dentate granule cells. In co-cultures of cortical neurons and NSC-34 cells overexpressing NEGR1, neurite growth of cortical neurons was enhanced and distal axons occupied an increased area of cells overexpressing NEGR1. Conversely, in organotypic slice co-cultures, Negr1-knockout (KO) hippocampus was less permissive for axons grown from EC of β-actin-enhanced green fluorescent protein (EGFP) mice compared to WT hippocampus. Neuroanatomical analysis revealed abnormalities of EC axons in the hippocampal dentate gyrus (DG) of Negr1-KO mice including increased numbers of axonal projections to the hilus. Neurotransmitter receptor ligand binding densities, a proxy of functional neurotransmitter receptor abundance, did not show differences in the DG of Negr1-KO mice but altered ligand binding densities to NMDA receptor and muscarinic acetylcholine receptors M1 and M2 were found in CA1 and CA3. Activity behavior, anxiety-like behavior and sensorimotor gating were not different between genotypes. However, Negr1-KO mice exhibited impaired social behavior compared to WT littermates. Moreover, Negr1-KO mice showed reversal learning deficits in the Morris water maze and increased susceptibility to pentylenetetrazol (PTZ)-induced seizures. Thus, our results from neuronal growth assays, neuroanatomical analyses and behavioral assessments provide first evidence that deficiency of the psychiatric disease-associated Negr1 gene may affect neuronal growth and behavior. These findings might be relevant to further evaluate the role of NEGR1 in cognitive and psychiatric disorders.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Neuronal Growth and Behavioral Alterations in Mice Deficient for the Psychiatric Disease-Associated Negr1 Gene

Singh

Loreth

Pöttker

et al. 2018

Front. Mol. Neurosci.

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“…Interestingly, our laboratory has recently demonstrated a role for the immunoglobulin superfamily CAM neuronal growth regulator 1 (NEGR1; Funatsu et al , 1999 ; Schafer et al , 2005 ) in regulating neuronal morphological maturation by a functional interaction with the RTK fibroblast growth factor receptor 2 (FGFR2) through modulation of the FGFR2-ERK signalling pathway in vitro ( Pischedda and Piccoli, 2015 ). Moreover, independent genetic studies have suggested a link among both NEGR1 and FGFR2 and brain disorders, including autism ( Marshall et al , 2008 ; Pinto et al , 2010 ; Hussman et al , 2011 ; Casey et al , 2012 ; Michaelson et al , 2012 ; Neale et al , 2012 ; Genovese et al , 2015 ).…”

Section: Introductionmentioning

confidence: 99%

NEGR1 and FGFR2 cooperatively regulate cortical development and core behaviours related to autism disorders in mice

Szczurkowska

Pischedda

Pinto

et al. 2018

Brain

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See Contreras and Hippenmeyer (doi:) for a scientific commentary on this article.Autism spectrum disorders (ASDs) are complex conditions with diverse aetiologies. Szczurkowska et al. demonstrate that two ASD-related molecules – FGFR2 and Negr1 – physically interact to act on the same downstream pathway, and regulate cortical development and ASD-relevant behaviours in mice. Identifying common mechanisms in ASDs may reveal targets for pharmacological intervention.

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“…A genome-wide copy number scan identified NEGR1 to be one of five new candidate genes involved in dyslexia ( Veerappa et al, 2013 ). A case study on two siblings with interstitial microdeletion of 1p31.1 involving only NEGR1 presented with learning and behavioral problems, hypotonia, hypermobility, scoliosis, and aortic root dilation ( Genovese et al, 2015 ). Further suggestive of the role NEGR1 has in brain disorders, NEGR1 is also elevated in the CSF of bipolar and depressed patients ( Maccarrone et al, 2013 ).…”

Section: Introductionmentioning

confidence: 99%

Glycosylphosphatidylinositol-Anchored Immunoglobulin Superfamily Cell Adhesion Molecules and Their Role in Neuronal Development and Synapse Regulation

Tan

Leshchyns’ka

Sytnyk

2017

Front. Mol. Neurosci.

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Immunoglobulin superfamily (IgSF) cell adhesion molecules (CAMs) are cell surface glycoproteins that not only mediate interactions between neurons but also between neurons and other cells in the nervous system. While typical IgSF CAMs are transmembrane molecules, this superfamily also includes CAMs, which do not possess transmembrane and intracellular domains and are instead attached to the plasma membrane via a glycosylphosphatidylinositol (GPI) anchor. In this review, we focus on the role GPI-anchored IgSF CAMs have as signal transducers and ligands in neurons, and discuss their functions in regulation of neuronal development, synapse formation, synaptic plasticity, learning, and behavior. We also review the links between GPI-anchored IgSF CAMs and brain disorders.

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Partial Deletion of Chromosome 1p31.1 Including only the Neuronal Growth Regulator 1 Gene in Two Siblings

Cited by 19 publications

References 14 publications

Neuronal Growth and Behavioral Alterations in Mice Deficient for the Psychiatric Disease-Associated Negr1 Gene

Neuronal Growth and Behavioral Alterations in Mice Deficient for the Psychiatric Disease-Associated Negr1 Gene

NEGR1 and FGFR2 cooperatively regulate cortical development and core behaviours related to autism disorders in mice

Glycosylphosphatidylinositol-Anchored Immunoglobulin Superfamily Cell Adhesion Molecules and Their Role in Neuronal Development and Synapse Regulation

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