Adherens Junctions in Myelinating Schwann Cells Stabilize Schmidt-Lanterman Incisures via Recruitment of p120 Catenin to E-Cadherin

Abstract

Schwann cell myelin contains highly compacted layers of membrane as well as noncompacted regions with a visible cytoplasm. One of these cytoplasmic compartments is the Schmidt-Lanterman incisure, which spirals through the compacted layers and is believed to help sustain the growth and function of compact myelin. Incisures contain adherens junctions (AJs), the key components of which are E-cadherin, its cytoplasmic partners called catenins, and F-actin. To explore in vivo the role of cadherin and catenins in incisures, E-cadherin mutant proteins that completely replace endogenous cadherin have been delivered to the cells using adenovirus. When the introduced cadherin lacked its extracellular domain, association of p120 catenin (p120ctn) with the cadherin did not occur, and incisures disappeared. Remarkably, the additional replacement of two phosphorylatable tyrosines by phenylalanine in the cytoplasmic tail of the mutant cadherin restored both p120ctn binding and incisure architecture, indicating that p120ctn recruitment is critical for incisures maintenance and might be regulated by phosphorylations. In addition, the ability of the p120ctn/cadherin complex to support incisures was blocked by mutation of the Rho GTPase regulatory region of the p120ctn, and downregulation of Rac1 activity at the junction reversed this inhibition. Because Rho GTPases regulate the state of the actin filaments, these findings suggest that one role of p120ctn in incisures is to organize the cytoskeleton at the AJ. Finally, developmental studies of Schwann cells demonstrated that p120ctn recruitment from the cytoplasm to the AJ occurs before the appearance of Rac1 GTPase and F-actin at the junction.

Tumor Suppressor Schwannomin/Merlin Is Critical for the Organization of Schwann Cell Contacts in Peripheral Nerves

“…This may involve the associated protein erbin (Rangwala et al, 2005) and Rac1 (Tricaud et al, 2005). In support of this hypothesis, ␤-catenin appears to stabilize SLIs through an inhibition of Rac1 (Tricaud et al, 2005) and schwannomin is capable of suppressing the recruitment of Rac1 to the plasma membrane (Okada et al, 2005).…”

“…Schwannomin immunoreactivity has been reported in SLIs (Scherer and Gutmann, 1996), suggesting that alteration of SLI numbers in schwannomin mutant mice may result from the role of schwannomin in stabilizing cadherin-based adherens junctions (Lallemand et al, 2003). This may involve the associated protein erbin (Rangwala et al, 2005) and Rac1 (Tricaud et al, 2005). In support of this hypothesis, ␤-catenin appears to stabilize SLIs through an inhibition of Rac1 (Tricaud et al, 2005) and schwannomin is capable of suppressing the recruitment of Rac1 to the plasma membrane (Okada et al, 2005).…”

“…In contrast to desert hedgehog-null mice, both shiverer (Sharghi-Namini et al, 2006) and schwannomin mutant mice displayed an increase in ␤-catenin and NF155 levels, indicating that these various mutations altered SLI numbers through different mechanisms. Little is known about the regulation of the formation of SLIs in which cadherin-mediated autotypic interactions are a key component (Tricaud et al, 2005;Perrin-Tricaud et al, 2007). Schwannomin immunoreactivity has been reported in SLIs (Scherer and Gutmann, 1996), suggesting that alteration of SLI numbers in schwannomin mutant mice may result from the role of schwannomin in stabilizing cadherin-based adherens junctions (Lallemand et al, 2003).…”

Identification of genes expressed by zebrafish oligodendrocytes using a differential microarray screen

“…Although the function of Ctnnd2 proteins in glial cells remains unknown, p120 ctn is necessary in myelinating Schwann cells for the formation of mature adherens junctions and a normal myelin sheath in mouse (Tricaud et al, 2005;Perrin-Tricaud et al, 2007).…”

Understanding the mechanisms of entrapment neuropathies

“…1 Although their function remains a subject of much debate, these incisures are likely to assist in the metabolic processes of the myelin sheath, including growth and maintenance. 44 The increase in SchmidtLanterman incisures along the axon thus most likely represents an increase in metabolic demand secondary to demyelination and remyelination in CNC injury. These findings in both human nerve tissue and animal models support the hypothesis that the decrease in nerve conduction velocity is a result of a new population of remyelinated fibers with thinner myelin and decreased internodal lengths.…”