The Mouse Mutation Claw Paw: Forelimb Deformity and Delayed Myelination throughout the Peripheral Nervous System

Henry, Earl Webb; Eicher, E.M.; Sidman, Richard L.

doi:10.1093/oxfordjournals.jhered.a111088

Cited by 19 publications

(34 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This phenotype was sometimes observed as early as birth, and was readily observable by P4. This limb phenotype is reminiscent of human patients with arthrogryposis multiplex congenita (AMC) (Bamshad et al, 2009) and has also been reported in mouse Adam22 mutants (Nishino et al, 2010) and mouse claw paw mutants (Henry et al, 1991;Darbas et al, 2004), which have a mutation in the Lgi4 gene (Bermingham et al, 2006). In addition to these limb posture abnormalities, sciatic nerves in Gpr126-/-mice were severely reduced in size with a hypomyelinated (i.e.…”

Section: Nerve and Limb Defects In Gpr126-/-micementioning

confidence: 58%

“…Gpr126-/-nerve pathology is also reminiscent of defects observed in Adam22 and Lgi4 mutants (Henry et al, 1991;Darbas et al, 2004;Sagane et al, 2005;Ozkaynak et al, 2010;Nishino et al, 2010). Adam22 is a receptor for Lgi4; Adam22 is expressed neuronally, and Lgi4 is secreted principally by Schwann cells in peripheral nerve (Sagane et al, 2008;Ozkaynak et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

“…Adam22 is a receptor for Lgi4; Adam22 is expressed neuronally, and Lgi4 is secreted principally by Schwann cells in peripheral nerve (Sagane et al, 2008;Ozkaynak et al, 2010). In addition to reduced Schwann cell myelination, Adam22 and Lgi4 mutant peripheral nerves also possess minifascicle pathologies throughout the endoneurium (Henry et al, 1991;Darbas et al, 2004;Sagane et al, 2005;Ozkaynak et al, 2010). Axonal sorting is also delayed in Lgi4 mutants (Darbas et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Gpr126 is essential for peripheral nerve development and myelination in mammals

et al. 2011

View full text Add to dashboard Cite

SUMMARYIn peripheral nerves, Schwann cells form the myelin sheath that insulates axons and allows rapid propagation of action potentials. Although a number of regulators of Schwann cell development are known, the signaling pathways that control myelination are incompletely understood. In this study, we show that Gpr126 is essential for myelination and other aspects of peripheral nerve development in mammals. A mutation in Gpr126 causes a severe congenital hypomyelinating peripheral neuropathy in mice, and expression of differentiated Schwann cell markers, including Pou3f1, Egr2, myelin protein zero and myelin basic protein, is reduced. Ultrastructural studies of Gpr126-/-mice showed that axonal sorting by Schwann cells is delayed, Remak bundles (non-myelinating Schwann cells associated with small caliber axons) are not observed, and Schwann cells are ultimately arrested at the promyelinating stage. Additionally, ectopic perineurial fibroblasts form aberrant fascicles throughout the endoneurium of the mutant sciatic nerve. This analysis shows that Gpr126 is required for Schwann cell myelination in mammals, and defines new roles for Gpr126 in axonal sorting, formation of mature non-myelinating Schwann cells and organization of the perineurium.

show abstract

Section: Nerve and Limb Defects In Gpr126-/-micementioning

confidence: 58%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Gpr126 is essential for peripheral nerve development and myelination in mammals

et al. 2011

View full text Add to dashboard Cite

show abstract

“…The fourth member of this protein family, LGI4, has been associated with childhood convulsions and absence epilepsy (Gu et al, 2004;Ishii et al, 2010). Moreover, targeted and spontaneous (claw paw mice; Lgi4 clp ) mutations in Lgi4 in mice cause severe congenital hypomyelination of the developing peripheral nervous system (PNS) and premature death (Bermingham et al, 2006;Henry et al, 1991;Nishino et al, 2010;Ozkaynak et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

“…The interaction between LGI4 and ADAM22 is required for timely axonal sorting and myelination (Bermingham et al, 2006;Henry et al, 1991;Sagane et al, 2005), developmental processes that involve extensive interactions between the axonal and Schwann cell membranes. ADAM23 is expressed in the PNS and in particular in Schwann cells (Dhaunchak et al, 2010), but its role in axonal sorting and myelination has not been explored.…”

Section: Introductionmentioning

confidence: 99%

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

Kegel¹,

Jaegle²,

Driegen³

et al. 2014

Journal of Cell Science

View full text Add to dashboard Cite

The cellular interactions that drive the formation and maintenance of the insulating myelin sheath around axons are only partially understood. Leucine-rich glioma-inactivated (LGI) proteins play important roles in nervous system development and mutations in their genes have been associated with epilepsy and amyelination. Their function involves interactions with ADAM22 and ADAM23 cell surface receptors, possibly in apposing membranes, thus attenuating cellular interactions. LGI4-ADAM22 interactions are required for axonal sorting and myelination in the developing peripheral nervous system (PNS). Functional analysis revealed that, despite their high homology and affinity for ADAM22, LGI proteins are functionally distinct. To dissect the key residues in LGI proteins required for coordinating axonal sorting and myelination in the developing PNS, we adopted a phylogenetic and computational approach and demonstrate that the mechanism of action of LGI4 depends on a cluster of three amino acids on the outer surface of the LGI4 protein, thus providing a structural basis for the mechanistic differences in LGI protein function in nervous system development and evolution.

show abstract

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

Booth

Kozar

bradley

et al. 2021

Glia

View full text Add to dashboard Cite

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.

show abstract

The Mouse Mutation Claw Paw: Forelimb Deformity and Delayed Myelination throughout the Peripheral Nervous System

Cited by 19 publications

References 22 publications

Gpr126 is essential for peripheral nerve development and myelination in mammals

Gpr126 is essential for peripheral nerve development and myelination in mammals

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

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

Contact Info

Product

Resources

About