LGI Proteins in the Nervous System

Kegel, Linde; Aunin, Eerik; Meijer, Dies; Bermingham, John R.

doi:10.1042/an20120095

Cited by 85 publications

(90 citation statements)

References 137 publications

(235 reference statements)

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“…Brains from Lgi1 +/+ and Lgi1 −/− mice were sectioned in 100-μm slices using a Leica Vibratome VT1200S. Slices were fixed in a PBS solution containing 4% PFA and 4% sucrose for 1 h, washed three times in PBS, and treated with NH 4 Cl for 30 min. Slices were then incubated for 2 h in blocking buffer (PBS, 10% goat serum and 0.1% Triton X-100).…”

Section: Methodsmentioning

confidence: 99%

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LGI1 tunes intrinsic excitability by regulating the density of axonal Kv1 channels

Seagar

Russier

Caillard

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

105

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Autosomal dominant epilepsy with auditory features results from mutations in leucine-rich glioma-inactivated 1 (LGI1), a soluble glycoprotein secreted by neurons. Animal models of LGI1 depletion display spontaneous seizures, however, the function of LGI1 and the mechanisms by which deficiency leads to epilepsy are unknown. We investigated the effects of pure recombinant LGI1 and genetic depletion on intrinsic excitability, in the absence of synaptic input, in hippocampal CA3 neurons, a classical focus for epileptogenesis. Our data indicate that LGI1 is expressed at the axonal initial segment and regulates action potential firing by setting the density of the axonal Kv1.1 channels that underlie dendrotoxin-sensitive D-type potassium current.LGI1 deficiency incurs a >50% down-regulation of the expression of Kv1.1 and Kv1.2 via a posttranscriptional mechanism, resulting in a reduction in the capacity of axonal D-type current to limit glutamate release, thus contributing to epileptogenesis.LGI1 | Kv1 channels | D-type current | intrinsic excitability | epilepsy

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Section: Methodsmentioning

confidence: 99%

“…ADEAF results from mutations in leucine-rich glioma-inactivated 1 (LGI1), a soluble glycoprotein secreted by neurons (1,2). Most ADEAF mutations impair secretion of the protein (3,4). Animal models of LGI1 depletion, including Lgi1 −/− mice (5)(6)(7)(8), mutant rats (9), and knockdown in zebrafish (10), all display spontaneous seizures.…”

mentioning

confidence: 99%

LGI1 tunes intrinsic excitability by regulating the density of axonal Kv1 channels

Seagar

Russier

Caillard

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

105

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“…LGI3 is a secreted protein (14) and was shown to be secreted by transfected 293T cells (15). The most abundant form of secreted LGI3 was the 60-kDa protein in 3T3-L1 pre-adipocytes (5).…”

Section: Resultsmentioning

confidence: 99%

“…

aging (14). It was important to distinguish previously described increase in EOTAXIN in the advanced CTCL patients (17) from normal aging.

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mentioning

confidence: 99%

Leucine‐rich glioma inactivated 3 is a melanogenic cytokine in human skin

Jeong

Kim

et al. 2014

Experimental Dermatology

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aging (14). It was important to distinguish previously described increase in EOTAXIN in the advanced CTCL patients (17) from normal aging. We found EOTAXIN and MIP-1B to be significantly higher across all age groups in patients with MF/SzS, suggestive of their relevance to the disease pathogenesis (Fig. S1).In conclusion, we demonstrate for the first time that the immune profiles of MF/SzS cluster closer to HIV and then to normal controls and demonstrate unique, cancer-specific and age-related immunological changes. It underscores an immunological dysbalance and immune-compromised state of patients with MF/SzS. AcknowledgementsWe thank Sue McCann, MRN for technical support with blood collection. This work was supported by SPORE NIH 5P50CA121973-03, Project 5 (to LJG) and UL1 RR024153 from the National Center for Research Resources (NCRR). Author contributionsLG and OA designed the study, analysed the data and wrote the paper. AL performed the Luminex assay. YL performed the statistical analysis. AL participated in the design of the work and the critical review of the paper. Conflict of interestThe authors state no conflict of interest. Supporting InformationAdditional Supporting Information may be found in the online version of this article: Figure S1. Age dependent biomarker expression in patient with MF/SzS and age matched controls. Table S1. Comparative analysis of soluble proteins. Medicine, Korea, Abstract: Recently, we demonstrated that leucine-rich glioma inactivated 3 (LGI3) is expressed in human skin. However, the effects of LGI3 on melanocytes remain unknown. The present study demonstrated that LGI3 can serve to stimulate melanogenesis without affecting cell viability. To determine the effects of LGI3 on melanin synthesis, normal human melanocytes and Mel-Ab cells were treated with recombinant LGI3 and melanin content was measured. Our results showed that LGI3 promoted melanin synthesis in both cell types. Moreover, upregulation of microphthalmia-associated transcription factor (MITF) and tyrosinase was observed at both the mRNA and protein levels via RT-PCR and Western blotting, respectively. Furthermore, immunohistochemical staining showed that the expression of LGI3 increased in the basal layer of melasma skin samples, whereas it decreased slightly in vitiligo samples. These results suggest that LGI3 may play a role as a melanogenic cytokine in human skin.

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“…Lgi4 is involved in glial cell proliferation and axon myelination in the peripheral nervous system (Kegel et al 2013). There is also evidence for a biological role in the central nervous system: polymorphisms in Lgi4 have been associated with central epilepsy conditions (Gu et al 2004;Ishii et al 2010).…”

Section: Discussionmentioning

confidence: 99%

Genetic Influences on Brain Gene Expression in Rats Selected for Tameness and Aggression

Heyne

Lautenschlaeger²,

Nelson

et al. 2014

Preprint

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Interindividual differences in many behaviors are partly due to genetic differences, but the identification of the genes and variants that influence behavior remains challenging. Here, we studied an F 2 intercross of two outbred lines of rats selected for tame and aggressive behavior toward humans for .64 generations. By using a mapping approach that is able to identify genetic loci segregating within the lines, we identified four times more loci influencing tameness and aggression than by an approach that assumes fixation of causative alleles, suggesting that many causative loci were not driven to fixation by the selection. We used RNA sequencing in 150 F 2 animals to identify hundreds of loci that influence brain gene expression. Several of these loci colocalize with tameness loci and may reflect the same genetic variants. Through analyses of correlations between allele effects on behavior and gene expression, differential expression between the tame and aggressive rat selection lines, and correlations between gene expression and tameness in F 2 animals, we identify the genes Gltscr2, Lgi4, Zfp40, and Slc17a7 as candidate contributors to the strikingly different behavior of the tame and aggressive animals. B EHAVIORAL differences among members of a species are in part due to genetic variation. The identification of the genes and variants that influence behavior remains challenging. In human genome-wide association studies of psychiatric and cognitive traits, the identified loci typically explain only a small fraction of the heritability, i.e., the additive genetic contribution to the trait (Watanabe et al. 2007;Hovatta and Barlow 2008;Deary et al. 2009;Otowa et al. 2009;Calboli et al. 2010;Terracciano et al. 2010;Flint and Munafo 2013;Rietveld et al. 2013;Sokolowska and Hovatta 2013). In experimental crosses in model species, especially between inbred lines, the identified loci (termed quantitative trait loci, QTL), often explain much more of the heritability (Lynch and Walsh 1998). However, in this design the spatial resolution is limited-the QTL are wide and contain many, sometimes hundreds of genes. With the exception of a handful of identified genes with quantitative effects on behavioral traits (Yalcin et al. 2004;Watanabe et al. 2007;McGrath et al. 2009;Bendesky et al. 2012;Goodson et al. 2012), gene identification is particularly difficult for behavioral QTL that often have modest effect sizes (Flint 2003;Willis-Owen and Flint 2006;Wright et al. 2006;Hovatta and Barlow 2008).The causal variants within a QTL can alter the protein sequence encoded by a gene or affect gene expression. Such Musunuru et al. 2010). A few eQTL studies have also recently been carried out to identify candidate genes for behavioral QTL (Hitzemann et al. 2004;De Jong et al. 2011;Saba et al. 2011;Kelly et al. 2012).Here, we studied two lines of rats (Rattus norvegicus) that, starting from one wild population, have been selected for increased tameness and increased aggression toward humans, respectively. These experimental...

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LGI Proteins in the Nervous System

Cited by 85 publications

References 137 publications

LGI1 tunes intrinsic excitability by regulating the density of axonal Kv1 channels

LGI1 tunes intrinsic excitability by regulating the density of axonal Kv1 channels

Leucine‐rich glioma inactivated 3 is a melanogenic cytokine in human skin

Genetic Influences on Brain Gene Expression in Rats Selected for Tameness and Aggression

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