Functional phylogenetic analysis of LGI proteins identifies an interaction motif crucial for myelination

Kegel, Linde; Jaegle, Martine; Driegen, Siska; Aunin, Eerik; Leslie, Kris; Fukata, Yuko; Watanabe, Masahiko; Fukata, Masaki; Meijer, Dies

doi:10.1242/jcs.154518

Cited by 4 publications

(10 citation statements)

References 19 publications

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“…Many studies in mammals have defined important regulators of Schwann cell development and myelination, including axonal neuregulin signals and their glial ErbB receptors and key Schwann cell transcription factors including Sox10, Oct6, Brn2, and Krox20 (Jessen and Mirsky 2005;Nave and Salzer 2006;Pereira et al 2012). Analysis of expression patterns, cell behavior, and mutant phenotypes in zebrafish indicates that the functions of these genes are broadly conserved among vertebrates (e.g., Kegel et al 2014;reviewed in Raphael and Talbot 2011).…”

Section: Schwann Cellsmentioning

confidence: 99%

Glial Cell Development and Function in Zebrafish

Lyons

Talbot

2014

Cold Spring Harb Perspect Biol

124

100

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The zebrafish is a premier vertebrate model system that offers many experimental advantages for in vivo imaging and genetic studies. This review provides an overview of glial cell types in the central and peripheral nervous system of zebrafish. We highlight some recent work that exploited the strengths of the zebrafish system to increase the understanding of the role of Gpr126 in Schwann cell myelination and illuminate the mechanisms controlling oligodendrocyte development and myelination. We also summarize similarities and differences between zebrafish radial glia and mammalian astrocytes and consider the possibility that their distinct characteristics may represent extremes in a continuum of cell identity. Finally, we focus on the emergence of zebrafish as a model for elucidating the development and function of microglia. These recent studies have highlighted the power of the zebrafish system for analyzing important aspects of glial development and function.

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Section: Schwann Cellsmentioning

confidence: 99%

Glial Cell Development and Function in Zebrafish

Lyons

Talbot

2014

Cold Spring Harb Perspect Biol

124

100

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“…Recent work by Kegel et al () has identified a novel mechanism of VGKCs clustering during PNS myelination involving the cell surface receptor ADAM23. We have verified the presence of ADAM23 at the CNS juxtaparanodes of the adult WT as well as Tag‐1 −/− callosal fibers during remyelination, co‐localized with VGKCs (Figure f).…”

Section: Resultsmentioning

confidence: 99%

“…A recent study has revealed the existence of an additional molecule at the juxtaparanode, ADAM23, which was found to co‐localize with Caspr2, CNTN2, and VGKCs at the area (Kegel et al, ). It has been suggested that ADAM22 and ADAM23 expression in apposing cell membranes at the juxtaparanode might be an additional mechanism of juxtaparanodal complex organization and/or stability possibly in an LGI4‐dependent manner, although this hypothesis needs further investigation (Kegel et al, ).…”

Section: Discussionmentioning

confidence: 99%

The function of contactin‐2/TAG‐1 in oligodendrocytes in health and demyelinating pathology

Zoupi

Savvaki

Kalemaki

et al. 2017

Glia

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The oligodendrocyte maturation process and the transition from the pre-myelinating to the myelinating state are extremely important during development and in pathology. In the present study, we have investigated the role of the cell adhesion molecule CNTN2/TAG-1 on oligodendrocyte proliferation, differentiation, myelination, and function during development and under pathological conditions. With the combination of in vivo, in vitro, ultrastructural, and electrophysiological methods, we have mapped the expression of CNTN2 protein in the oligodendrocyte lineage during the different stages of myelination and its involvement on oligodendrocyte maturation, branching, myelin-gene expression, myelination, and axonal function. The cuprizone model of central nervous system demyelination was further used to assess CNTN2 in pathology. During development, CNTN2 can transiently affect the expression levels of myelin and myelin-regulating genes, while its absence results in reduced oligodendrocyte branching, hypomyelination of fiber tracts and impaired axonal conduction. In pathology, CNTN2 absence does not affect the extent of de- and remyelination. However during remyelination, a novel, CNTN2-independent mechanism is revealed that is able to recluster voltage gated potassium channels (VGKCs) resulting in the improvement of fiber conduction.

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“…Dorsal root ganglia (DRG) were dissected from mouse embryos at embryonic day 13 or postnatal day 4–6 pups (sex not determined) according to established protocols (Kegel et al, 2014; Kleitman et al, 2002; Sleigh et al, 2016). Cells were seeded as explants onto Matrigel (BD Biosciences)/poly‐D‐lysine (Sigma)‐coated 16 mm coverslips (Thermo Scientific) and maintained in MEM (Gibco) supplemented with 3% Fetal Bovine serum (FBS), 50 ng/ml NGF and Penicillin and Streptomycin (M1 medium) in a 5%CO 2 incubator at 37°C.…”

Section: Methodsmentioning

confidence: 99%

“…Mice carrying homozygous Lgi4 mutant alleles (the “claw paw” allele Lgi4 Clp or Lgi4 ∆1–3 ) or homozygous Adam22 ( Adam22 ∆ 1 ) mutant alleles have a severely reduced lifespan, exhibit pronounced joint contractures (Bermingham et al, 2006; Darbas et al, 2004; Henry et al, 1991; Nishino et al, 2010; Ozkaynak et al, 2010; Sagane et al, 2005) and congenital hypomyelination of the PNS. Functional studies identified a patch of amino acids within the Epitempin domain of Lgi4 that is crucially involved in promoting myelination but distinct from its Adam22 binding interface (Kegel et al, 2014) (Figure 1a).…”

Section: Introductionmentioning

confidence: 99%

Characterizing the molecular etiology of arthrogryposis multiplex congenita in patients with LGI4 mutations

Booth

Kozar

bradley

et al. 2021

Glia

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Disruption of axon-glia interactions in the peripheral nervous system has emerged as a major cause of arthrogryposis multiplex congenita (AMC), a condition characterized by multiple congenital postural abnormalities involving the major joints. Several genes crucially important to the biology of Schwann cells have now been implicated with AMC. One such gene is LGI4 which encodes a secreted glycoprotein. LGI4 is expressed and secreted by Schwann cells and binds its receptor ADAM22 on the axonal membrane to drive myelination. Homozygous mutations in LGI4 or ADAM22 results in severe congenital hypomyelination and joint contractures in mice. Recently bi-allelic LGI4 loss of function mutations has been described in three unrelated families with severe AMC. Two individuals in a fourth, non-consanguineous family were found to be compound heterozygous for two LGI4 missense mutations. It is not known how these missense mutations affect the biology of LGI4. Here we investigated whether these missense mutations affected the secretion of the protein, its ADAM22 binding capacity, or its myelination-promoting function. We demonstrate that the mutations largely affect the progression of the mutant protein through the endomembrane system resulting in severely reduced expression. Importantly, binding to ADAM22 and myelination-promoting activity appear largely unaffected, suggesting that treatment with chemical chaperones to improve secretion of the mutant proteins might prove beneficial.

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Functional phylogenetic analysis of LGI proteins identifies an interaction motif crucial for myelination

Cited by 4 publications

References 19 publications

Glial Cell Development and Function in Zebrafish

Glial Cell Development and Function in Zebrafish

The function of contactin‐2/TAG‐1 in oligodendrocytes in health and demyelinating pathology

Characterizing the molecular etiology of arthrogryposis multiplex congenita in patients with LGI4 mutations

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