The L1 Family of Cell Adhesion Molecules: A Sickening Number of Mutations and Protein Functions

Hortsch, Michael; Nagaraj, Kakanahalli; Mualla, Rula

doi:10.1007/978-1-4614-8090-7_9

Cited by 43 publications

(16 citation statements)

References 245 publications

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“…Reversible binding of the L1-CAM cytoplasmic domain to Ankyrin is regulated by dephosphorylation of a tyrosine residue (Y1229) in a conserved motif FIGQ/AY (Figure 3D; Garver et al, 1997;Yamasaki et al, 1997;Needham et al, 2001;Guan and Maness, 2010). Mutation of Tyr1229 in L1 to histidine occurs in the L1 syndrome of intellectual disability (Hortsch et al, 2014). A mouse model of this disorder harbors an L1 knock-in point mutation (Tyr1229His) that impairs L1-Ankyrin binding (Buhusi et al, 2008).…”

Section: Role Of Ankyrin Interaction With Neural Adhesion Molecules In Synaptic Stabilizationmentioning

confidence: 99%

Molecular Mechanisms of L1 and NCAM Adhesion Molecules in Synaptic Pruning, Plasticity, and Stabilization

Duncan

Murphy

Maness

2021

Front. Cell Dev. Biol.

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Mammalian brain circuits are wired by dynamic formation and remodeling during development to produce a balance of excitatory and inhibitory synapses. Synaptic regulation is mediated by a complex network of proteins including immunoglobulin (Ig)- class cell adhesion molecules (CAMs), structural and signal-transducing components at the pre- and post-synaptic membranes, and the extracellular protein matrix. This review explores the current understanding of developmental synapse regulation mediated by L1 and NCAM family CAMs. Excitatory and inhibitory synapses undergo formation and remodeling through neuronal CAMs and receptor-ligand interactions. These responses result in pruning inactive dendritic spines and perisomatic contacts, or synaptic strengthening during critical periods of plasticity. Ankyrins engage neural adhesion molecules of the L1 family (L1-CAMs) to promote synaptic stability. Chondroitin sulfates, hyaluronic acid, tenascin-R, and linker proteins comprising the perineuronal net interact with L1-CAMs and NCAM, stabilizing synaptic contacts and limiting plasticity as critical periods close. Understanding neuronal adhesion signaling and synaptic targeting provides insight into normal development as well as synaptic connectivity disorders including autism, schizophrenia, and intellectual disability.

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Section: Role Of Ankyrin Interaction With Neural Adhesion Molecules In Synaptic Stabilizationmentioning

confidence: 99%

Molecular Mechanisms of L1 and NCAM Adhesion Molecules in Synaptic Pruning, Plasticity, and Stabilization

Duncan

Murphy

Maness

2021

Front. Cell Dev. Biol.

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“…L1CAMs coordinate multiple adhesion and signaling mechanisms in nervous system development, maintenance and function (Brummendorf et al, 1998;Cohen et al, 1998). As a result, mutations in L1 family members result in a wide range of human neurological abnormalities, including CRASH disorder (corpus callosum hypoplasia, retardation, adducted thumbs, spastic paraplegia, and hydrocephalus) (Nagaraj et al, 2014). Vertebrates typically encode four L1 family members (L1, CHL1, Neurofascin and NrCAM), whereas invertebrates contain one or two L1 orthologs (Brummendorf et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Harmonization of L1CAM expression facilitates axon outgrowth and guidance of a motor neuron

et al. 2020

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Brain development requires precise regulation of axon outgrowth, guidance and termination by multiple signaling and adhesion molecules. How the expression of these neurodevelopmental regulators is transcriptionally controlled is poorly understood. The Caenorhabditis elegans SMD motor neurons terminate axon outgrowth upon sexual maturity and partially retract their axons during early adulthood. Here we show that C-Terminal Binding Protein-1 (CTBP-1), a transcriptional corepressor, is required for correct SMD axonal development. Loss of CTBP-1 causes multiple defects in SMD axon development: premature outgrowth, defective guidance, delayed termination and absence of retraction. CTBP-1 controls SMD axon guidance by repressing the expression of SAX-7 - a L1 cell adhesion molecule (L1CAM). CTBP-1-regulated repression is crucial as deregulated SAX-7/L1CAM causes severely aberrant SMD axons. We found that axonal defects caused by deregulated SAX-7/L1CAM are dependent on a distinct L1CAM, called LAD-2, which itself plays a parallel role in SMD axon guidance. Our results reveal that harmonization of L1CAM expression controls the development and maturation of a single neuron.

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“…The cell adhesion molecule L1 (also known as L1CAM) plays crucial roles in a number of cellular processes during development of the central and peripheral nervous systems. It is involved in regulation of cell proliferation and migration, and participates in neuritogenesis, fasciculation of axons, myelination, synaptogenesis, synaptic plasticity and regeneration after acute and during chronic neural impairments (for reviews, see Kamiguchi et al, 1998;Hortsch, 2000;Loers and Schachner, 2007;Maness and Schachner, 2007;Schmid and Maness, 2008;Hortsch et al, 2014;Sytnyk et al, 2017). In the mouse, genetic ablation of L1 leads to malformation of the brain and of other L1-expressing organs, such as the kidney and enteric nervous system (Dahme et al, 1997;Debiec et al, 2002;Anderson et al, 2006;Wallace et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

A fragment of adhesion molecule L1 is imported into mitochondria, and regulates mitochondrial metabolism and trafficking

Kraus

Kleene

Braren

et al. 2018

Journal of Cell Science

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The cell adhesion molecule L1 (also known as L1CAM) plays important roles in the mammalian nervous system under physiological and pathological conditions. We have previously reported that proteolytic cleavage of L1 by myelin basic protein leads to the generation of a 70 kDa transmembrane L1 fragment (L1-70) that promotes neuronal migration and neuritogenesis. Here, we provide evidence that L1-70 is imported from the cytoplasm into mitochondria. Genetic ablation of L1, inhibition of mitochondrial import of L1-70 or prevention of myelin basic protein-mediated generation of L1-70 all lead to reduced mitochondrial complex I activity, and impaired mitochondrial membrane potential, fusion, fission and motility, as well as increased retrograde transport. We identified NADH dehydrogenase ubiquinone flavoprotein 2 as a binding partner for L1, suggesting that L1-70 interacts with this complex I subunit to regulate complex I activity. The results of our study provide insights into novel functions of L1 in mitochondrial metabolism and cellular dynamics. These functions are likely to ameliorate the consequences of acute nervous system injuries and chronic neurodegenerative diseases.

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The L1 Family of Cell Adhesion Molecules: A Sickening Number of Mutations and Protein Functions

Cited by 43 publications

References 245 publications

Molecular Mechanisms of L1 and NCAM Adhesion Molecules in Synaptic Pruning, Plasticity, and Stabilization

Molecular Mechanisms of L1 and NCAM Adhesion Molecules in Synaptic Pruning, Plasticity, and Stabilization

Harmonization of L1CAM expression facilitates axon outgrowth and guidance of a motor neuron

A fragment of adhesion molecule L1 is imported into mitochondria, and regulates mitochondrial metabolism and trafficking

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