Adenomatous polyposis coli regulates radial axonal sorting and myelination in the PNS

Abstract

The tumor suppressor protein adenomatous polyposis coli (APC) is multifunctional -it participates in the canonical Wnt/β-catenin signal transduction pathway as well as modulating cytoskeleton function. Although APC is expressed by Schwann cells, the role that it plays in these cells and in the myelination of the peripheral nervous system (PNS) is unknown. Therefore, we used the Cre-lox approach to generate a mouse model in which APC expression is specifically eliminated from Schwann cells. These mice display hindlimb weakness and impaired axonal conduction in sciatic nerves. Detailed morphological analyses revealed that APC loss delays radial axonal sorting and PNS myelination. Furthermore, APC loss delays Schwann cell differentiation in vivo, which correlates with persistent activation of the Wnt signaling pathway and results in perturbed extension of Schwann cell processes and disrupted lamellipodia formation. In addition, APC-deficient Schwann cells display a transient diminution of proliferative capacity. Our data indicate that APC is required by Schwann cells for their timely differentiation to mature, myelinating cells and plays a crucial role in radial axonal sorting and PNS myelination.

Assembly of Metallacages into Soft Suprastructures with Dimensions of up to Micrometers and the Formation of Composite Materials

“…60 Inspired by the preparation of perylene/microneedles composites, we selected chlorophyll-a (Chl-a) as a model of a fat-soluble biomolecule for its potential application in the energy field (Chl-a serves as the light-absorbing and energy-transferring components in the assemblies). We selected vitamin B 12 as a model of a water-soluble biomolecule for its potential application in biomedical sciences; 61 for example, it could modulate the transcriptome of the skin microbiota in acne pathogenesis. 62 Herein, we demonstrate the preparation of Chl-a- and vitamin B 12 -containing microflowers by using cage 1 -based microneedles as a platform.…”

Wnt/Beta-Catenin Signaling Regulation and a Role for Biomolecular Condensates

“…At least some APC proteins also regulate actin dynamics, working together with Diaphanous (Breitsprecher et al, 2012; Jaiswal et al, 2013), to control focal adhesion turnover (Juanes et al, 2017). When considering cytoskeletal effects of APC loss, however, it is critical to rule out places where Wnt signaling itself regulates downstream cytoskeletal events (e.g., Elbaz et al, 2016;Eom et al, 2014;Hayden et al, 2007;Nakagawa et al, 2017;Yokota et al, 2009). Other destruction complex or signalosome proteins also have cytoskeletal roles.…”

Schwann cell interactions during the development of the peripheral nervous system

“…These findings suggest that WNT signalling may have an important temporal role in Schwann cells, as a facilitator of radial sorting, but as an inhibitor of myelination. Conversely, conditional ablation of APC in Schwann cells appears to inhibit proper radial sorting, although this may be due to APC's additional role as a cytoskeletal interactor and polarity determinant and consequent effect on the polarized Schwann cell extension necessary for radial sorting (Elbaz et al, 2016). In agreement, investigation of β-catenin downstream of N-cadherin signalling suggests that β-catenin is important for establishing Schwann cell polarity and thus the onset of myelination (Lewallen et al, 2011).…”

“…The key downstream target of canonical WNT signaling is the transcription factor β-catenin and Grigoryan et al (2013) found ablation of β-catenin from Schwann cells to cause mild radial sorting delay and constitutively active β-catenin to enhance radial sorting. Despite this effect on radial sorting, constitutively active β-catenin results in thinner myelin sheaths (Grigoryan et al, 2013), as does Schwann cell ablation of adenomatous polyposis coli (APC, Elbaz et al, 2016), a member of the β-catenin destruction complex, and thus, inhibitor of β-catenin. These findings suggest that WNT signaling may have an important temporal role in Schwann cells, as a facilitator of radial sorting, but as an inhibitor of myelination.…”

“…GABA released from axons is thought to signal through GABA-B receptors in Remak Schwann cells to inhibit the expression of myelin genes. The expression of molecules represented by this figure may not be strictly limited to the developmental or differentiation stage depicted due to APC's additional role as a cytoskeletal interactor and polarity determinant and consequent effect on the polarized Schwann cell extension necessary for radial sorting (Elbaz et al, 2016). In agreement, investigation of β-catenin downstream of N-cadherin (also known as cadherin 2) signaling suggests that β-catenin is important for establishing Schwann cell polarity, and thus, the onset of myelination (Lewallen et al, 2011).…”