Sox2 controls Schwann cell self-organization through fibronectin fibrillogenesis

Abstract

The extracellular matrix is known to modulate cell adhesion and migration during tissue regeneration. However, the molecular mechanisms that fine-tune cells to extra-cellular matrix dynamics during regeneration of the peripheral nervous system remain poorly understood. Using the RSC96 Schwann cell line, we show that Sox2 directly controls fibronectin fibrillogenesis in Schwann cells in culture, to provide a highly oriented fibronectin matrix, which supports their organization and directional migration. We demonstrate that Sox2 regulates Schwann cell behaviour through the upregulation of multiple extracellular matrix and migration genes as well as the formation of focal adhesions during cell movement. We find that mouse primary sensory neurons and human induced pluripotent stem cell-derived motoneurons require the Sox2-dependent fibronectin matrix in order to migrate along the oriented Schwann cells. Direct loss of fibronectin in Schwann cells impairs their directional migration affecting the alignment of the axons in vitro. Furthermore, we show that Sox2 and fibronectin are coexpressed in proregenerative Schwann cells in vivo in a time-dependent manner during sciatic nerve regeneration. Taken together, our results provide new insights into the mechanisms by which Schwann cells regulate their own extracellular microenvironment in a Sox2-dependent manner to ensure the proper migration of neurons.

Single-Cell Probe Force Studies to Identify Sox2 Overexpression-Promoted Cell Adhesion in MCF7 Breast Cancer Cells

“…However, the reduction in cell-cell adhesion was claimed to be partly due to the loss of E-cadherin expression and the enhanced expression of N-cadherins, which is not expressed in these cells, as reported by Smolyakov and colleagues [49], suggesting that other adhesion receptors may be implicated. Sox2 has also been shown to affect cell-ECM interactions in other systems, for example, cell adhesion-and ECM-related genes were found to be significantly up-regulated upon Sox2 overexpression in Schwann cells, and Sox2 was identified as a key regulator of ECM remodeling during Schwann cell clustering, directional migration, and axonal guidance in vitro [52].…”

Schwann cells and trigeminal neuralgia

“…They migrate and differentiate from neural crest cells and develop into precursor SCs that enter the SC 10 . Recent studies have reported an association between the up-regulation of transcription factor sox2 and the entry of neural crest precursor cells into the SC lineage [11][12][13] . In addition, transcription factor FoxD3 might be an important factor for the differentiation of neural crest cells into the SC lineage.…”

“…In addition to proliferation and differentiation of neural crest cells into the SC lineage, sox10 also regulates the myelination of SCs 15 . These transcription factors might affect TN by regulating Schwann cell regeneration and myelin formation 12,16,17 . With extensive cell proliferation and differentiation, the SCs separate the axons into bundles, a process known as "radial sorting."…”

“… 10 Recent studies have reported an association between the upregulation of transcription factor sox2 and the entry of neural crest precursor cells into the SC lineage. 11 – 13 In addition, transcription factor FoxD3 might be an important factor for the differentiation of neural crest cells into the SC lineage. This is because its expression inhibits the development of neurons and melanocytes, which are the other differentiation lineages of migrating neural crest cells.…”

“… 15 These transcription factors might affect TN by regulating SC regeneration and myelin formation. 12 , 16 , 17 With extensive cell proliferation and differentiation, the SCs separate the axons into bundles, a process known as “radial sorting.” Here, the SCs wrap around the axons and separate them into small bundles. At this time, SCs are divided into either myelinating or nonmyelinating SCs.…”