L1 syndrome mutations impair neuronal L1 function at different levels by divergent mechanisms

Schäfer, Michael K. E.; Nam, Yun-Chung; Moumen, Anice; Keglowich, Laura; Bouché, Elisabeth; Küffner, Mercedes; Bock, Hans H.; Rathjen, Fritz G.; Raoul, Cédric; Frotscher, Michael

doi:10.1016/j.nbd.2010.05.029

Cited by 38 publications

(64 citation statements)

References 67 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, the axonal localization of NgCAM/L1 is one example of targeting mediated by the extracellular domain of a CAM (45,46). L1 is important in axon growth and synapse formation, and disruption of its axonal localization in humans causes L1 syndrome (47).…”

Section: Discussionmentioning

confidence: 99%

“…L1 is important in axon growth and synapse formation, and disruption of its axonal localization in humans causes L1 syndrome (47). Two missense mutants that occur in the extracellular domain of L1 were recently found to reduce L1 surface expression in heterologous cells due to partial ER retention (46). Similar to SALM1, this retention causes a change in the glycosylation pattern of L1.…”

Section: Discussionmentioning

confidence: 99%

“…Similar to SALM1, this retention causes a change in the glycosylation pattern of L1. In neurons, these mutants reduce axonal surface localization or mistarget L1 to dendrites (46). Wisco et al (48) have reported that NgCAM/LI can also be indirectly targeted to axons by transcytosis from dendrites mediated by an endocytosis motif (YRSL).…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Dileucine and PDZ-binding Motifs Mediate Synaptic Adhesion-like Molecule 1 (SALM1) Trafficking in Hippocampal Neurons

Seabold

Wang

Petralia

et al. 2012

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Dileucine and PDZ-binding Motifs Mediate Synaptic Adhesion-like Molecule 1 (SALM1) Trafficking in Hippocampal Neurons

Seabold

Wang

Petralia

et al. 2012

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Mutations in the human L1 gene cause brain lesions and neurological abnormalities. Some of these mutations also disrupt L1 homophilic binding (13)(14)(15)(16). We noted that brain lesions in children with FASD resemble those of children with mutations in the gene for L1 and demonstrated that concentrations of ethanol attained after just one or two drinks inhibit L1 adhesion in cerebellar granule neurons, neural cell lines, and NIH/3T3 fibroblasts (17)(18)(19).…”

mentioning

confidence: 96%

Mitogen-activated protein kinase modulates ethanol inhibition of cell adhesion mediated by the L1 neural cell adhesion molecule

Dou

Wilkemeyer

Menkari

et al. 2013

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

View full text Add to dashboard Cite

There is a genetic contribution to fetal alcohol spectrum disorders (FASD), but the identification of candidate genes has been elusive. Ethanol may cause FASD in part by decreasing the adhesion of the developmentally critical L1 cell adhesion molecule through interactions with an alcohol binding pocket on the extracellular domain. Pharmacologic inhibition or genetic knockdown of ERK2 did not alter L1 adhesion, but markedly decreased ethanol inhibition of L1 adhesion in NIH/3T3 cells and NG108-15 cells. Likewise, leucine replacement of S1248, an ERK2 substrate on the L1 cytoplasmic domain, did not decrease L1 adhesion, but abolished ethanol inhibition of L1 adhesion. Stable transfection of NIH/3T3 cells with human L1 resulted in clonal cell lines in which L1 adhesion was consistently sensitive or insensitive to ethanol for more than a decade. ERK2 activity and S1248 phosphorylation were greater in ethanol-sensitive NIH/3T3 clonal cell lines than in their ethanol-insensitive counterparts. Ethanol-insensitive cells became ethanol sensitive after increasing ERK2 activity by transfection with a constitutively active MAP kinase kinase 1. Finally, embryos from two substrains of C57BL mice that differ in susceptibility to ethanol teratogenesis showed corresponding differences in MAPK activity. Our data suggest that ERK2 phosphorylation of S1248 modulates ethanol inhibition of L1 adhesion by inside-out signaling and that differential regulation of ERK2 signaling might contribute to genetic susceptibility to FASD. Moreover, identification of a specific locus that regulates ethanol sensitivity, but not L1 function, might facilitate the rational design of drugs that block ethanol neurotoxicity. P renatal alcohol exposure causes fetal alcohol spectrum disorders (FASD) in up to 2-5% of school-age children and is the leading preventable cause of mental retardation in the Western world (1, 2). The prevalence and presentation of FASD are influenced by the quantity, frequency, and timing of drinking and are modified by a variety of environmental, nutritional, epigenetic, and genetic factors (3-7). The observation that there is greater concordance for fetal alcohol syndrome (FAS) in monozygotic twins than in dizygotic twins suggests that there are susceptibility genes for FASD (8); however, their identification remains elusive. The identification of molecular pathways that regulate sensitivity to ethanol teratogenesis would be helpful in the search for FASD susceptibility genes.One potentially important target of ethanol in the pathogenesis of FASD is the developmentally critical immunoglobulin neural cell adhesion molecule, L1. The homophilic binding of L1 molecules on adjacent cells mediates neuronal migration, axon guidance, and axon fasciculation (9)-developmental events that are disrupted in FASD (10-12). Mutations in the human L1 gene cause brain lesions and neurological abnormalities. Some of these mutations also disrupt L1 homophilic binding (13-16). We noted that brain lesions in children with FASD resemble those of child...

show abstract

“…The in vitro effects have been observed when L1CAM has been either overexpressed in diverse types of primary neurons and/or offered as a substrate for developing neurons (Cheng and Lemmon 2004;Cheng et al 2005;Hoffman et al 2008;Moon and Gomez 2010;Schäfer et al 2010b). In addition to studies in developing primary neuronal cultures, L1CAM overexpression has been shown to promote axonal branching in mature CA3 pyramidal neurons of organotypic hippocampal slice cultures.…”

Section: L1cam-mediated Axon Branching In Vitromentioning

confidence: 99%

Role of L1CAM for axon sprouting and branching

Schäfer

Frotscher²

2012

Cell Tissue Res

Self Cite

View full text Add to dashboard Cite

The central nervous system (CNS) has been traditionally considered as an organ that fails to regenerate in response to injury. Indeed, the lesioned CNS faces a number of obstacles during regeneration, including an overall non-permissive environment for axonal regeneration. However, research during the last few decades has identified axon sprouting as an anatomical correlate for the regenerative capability of the CNS to establish new connections. The immunoglobulin superfamily member L1CAM has been shown to promote the capability of neurons for regenerative axon sprouting and to improve behavioral outcomes after CNS injury. Here, we discuss the cell-autonomous role of L1CAM for axon sprouting in experimental rodent injury models and highlight the molecular interactions of L1CAM with ankyrins, ezrin-radixin-moesin proteins and the Sema3A/Neuropilin ligand-receptor complex in the context of axonal branching.

show abstract

L1 syndrome mutations impair neuronal L1 function at different levels by divergent mechanisms

Cited by 38 publications

References 67 publications

Dileucine and PDZ-binding Motifs Mediate Synaptic Adhesion-like Molecule 1 (SALM1) Trafficking in Hippocampal Neurons

Dileucine and PDZ-binding Motifs Mediate Synaptic Adhesion-like Molecule 1 (SALM1) Trafficking in Hippocampal Neurons

Mitogen-activated protein kinase modulates ethanol inhibition of cell adhesion mediated by the L1 neural cell adhesion molecule

Role of L1CAM for axon sprouting and branching

Contact Info

Product

Resources

About