LINGO-1 is a component of the Nogo-66 receptor/p75 signaling complex

Mi, Sha; Lee, Xinhua; Shao, Zhaohui; Thill, Greg; Ji, Benxiu; Relton, Jane K.; Levesque, Melissa; Allaire, Norm; Perrin, Steve; Sands, Bryan; Crowell, Thomas; Cate, Richard L.; McCoy, John; Pepinsky, R. Blake

doi:10.1038/nn1188

Cited by 754 publications

(650 citation statements)

References 38 publications

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“…Other lines of evidence have revealed the requirement for another co-receptor known as LINGO1, a transmem brane protein that can bind to both NgR and p75 (REF. 69). Co-expression of all three receptor components, including NgR, p75 or TROY, and LINGO1, is sufficient to allow non-neuronal cells to respond to myelin inhibitors by activating the downstream signal RhoA 67,68 .…”

Section: Receptor Mechanisms For Myelin Inhibitionmentioning

confidence: 99%

Glial inhibition of CNS axon regeneration

2006

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Damage to the adult CNS often leads to persistent deficits due to the inability of mature axons to regenerate after injury. Mounting evidence suggests that the glial environment of the adult CNS, which includes inhibitory molecules in CNS myelin as well as proteoglycans associated with astroglial scarring, might present a major hurdle for successful axon regeneration. Here, we evaluate the molecular basis of these inhibitory influences and their contributions to the limitation of longdistance axon repair and other types of structural plasticity. Greater insight into glial inhibition is crucial for developing therapies to promote functional recovery after neural injury.The nervous system has the remarkable ability to adapt and respond to various stimuli, ranging from physiological experiences associated with learning and memory, to pathological insults such as traumatic injury, stroke or neurodegenerative diseases. In addition to plasticity at the functional level, nervous system responses might also occur in the form of structural remodelling. In vivo imaging studies have shown that sensory experience can drive the formation and elimination of synapses, and that these changes might underlie the adaptive remodelling of neural circuits 1,2 . Similarly, neural injury is often accompanied by a transient period of anatomical remodel ling in the form of local sprouting at the lesion site 3 . However, although many CNS neurons can survive for years after axotomy, the severed axons ultimately fail to regenerate beyond the lesion site, in contrast to those in the PNS or embryonic nervous system. Recent evidence is beginning to reveal intriguing parallels between some of the molecular mechanisms that affect the different forms of structural plasticity, including both short-range remodelling and long-distance axon regrowth. Therefore, targeting these mechanisms might not only promote the regeneration of damaged nerve fibres, but might also enhance axon sprouting and plasticity after CNS injury. Here, we describe recent progress in under standing the inhibitory components of the adult glial environment, as well as the neuronal receptor complexes and downstream signals that mediate their effects. The limited success in targeting these pathways in vivo will then be evaluated. Finally, we discuss the physiological roles of glial inhibition in the intact nervous system, and their implications for the development of strategies to promote functional recovery after adult CNS injury. The role of extrinsic inhibitionThe regeneration failure in the adult CNS might be partly attributed to the gradual decline in the intrinsic growth ability of neurons as the animal matures. Ramón y Cajal described that, © 2006 Nature Publishing Group Correspondence to Z.H. e-mail: E-mail: zhigang.he@childrens.harvard.edu. Competing interests statementThe authors declare no competing financial interests. DATABASES NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript after injury, the ends of lesioned axons become swollen in...

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Section: Receptor Mechanisms For Myelin Inhibitionmentioning

confidence: 99%

Glial inhibition of CNS axon regeneration

2006

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“…LINGO-1 LINGO-1 was identified in a search for CNS-specific leucine rich repeat proteins [51]. It has been shown to regulate axon outgrowth by interaction with the Nogo-66 receptor complex.…”

Section: Pharmacological Targets Of Remyelinationmentioning

confidence: 99%

Myelin Regeneration in Multiple Sclerosis: Targeting Endogenous Stem Cells

et al. 2011

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Regeneration of myelin sheaths (remyelination) after central nervous system demyelination is important to restore saltatory conduction and to prevent axonal loss. In multiple sclerosis, the insufficiency of remyelination leads to the irreversible degeneration of axons and correlated clinical decline. Therefore, a regenerative strategy to encourage remyelination may protect axons and improve symptoms in multiple sclerosis. We highlight recent studies on factors that influence endogenous remyelination and potential promising pharmacological targets that may be considered for enhancing central nervous system remyelination.

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“…It has been demonstrated that LINGO1 is part of the LINGO1-RTN4R/ NGFR receptor complex that negatively regulates myelination, oligodendrocyte differentiation, axon regeneration, and neuronal survival. 32,33 Increased LINGO1 expression has been found in various animal models with CNS injury and in the CNS diseases in humans. 34 In transgenic mice, overexpression of LINGO1 causes reduction in myelination, and lessdifferentiated oligodendrocytes were observed.…”

Section: Discussionmentioning

confidence: 99%

Biallelic variants in LINGO1 are associated with autosomal recessive intellectual disability, microcephaly, speech and motor delay

Ansar

Riazuddin

Sarwar

et al. 2018

Genetics in Medicine

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Purpose: To elucidate the novel molecular cause in two unrelated consanguineous families with autosomal recessive intellectual disability.Methods: A combination of homozygosity mapping and exome sequencing was used to locate the plausible genetic defect in family F162, while only exome sequencing was followed in the family PKMR65. The protein 3D structure was visualized with the University of California-San Francisco Chimera software.Results: All five patients from both families presented with severe intellectual disability, aggressive behavior, and speech and motor delay. Four of the five patients had microcephaly. We identified homozygous missense variants in LINGO1, p.(Arg290His) in family F162 and p.(Tyr288Cys) in family PKMR65. Both variants were predicted to be pathogenic, and segregated with the phenotype in the respective families. Molecular modeling of LINGO1 suggests that both variants interfere with the glycosylation of the protein.Conclusion: LINGO1 is a transmembrane receptor, predominantly found in the central nervous system. Published loss-offunction studies in mouse and zebrafish have established a crucial role of LINGO1 in normal neuronal development and central nervous system myelination by negatively regulating oligodendrocyte differentiation and neuronal survival. Taken together, our results indicate that biallelic LINGO1 missense variants cause autosomal recessive intellectual disability in humans.

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LINGO-1 is a component of the Nogo-66 receptor/p75 signaling complex

Cited by 754 publications

References 38 publications

Glial inhibition of CNS axon regeneration

Glial inhibition of CNS axon regeneration

Myelin Regeneration in Multiple Sclerosis: Targeting Endogenous Stem Cells

Biallelic variants in LINGO1 are associated with autosomal recessive intellectual disability, microcephaly, speech and motor delay

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