Enteric neural crest-derived cells promote their migration by modifying their microenvironment through tenascin-C production

Abstract

The enteric nervous system (ENS) is derived from vagal and sacral neural crest cells that migrate, proliferate, and differentiate into enteric neurons and glia within the gut wall. The mechanisms regulating enteric neural crest-derived cell (ENCC) migration are poorly characterized despite the importance of this process in gut formation and function. Characterization of genes involved in ENCC migration is essential to understanding ENS development and could provide targets for treatment of human ENS disorders. We identified the extracellular matrix glycoprotein tenascin-C (TNC) as an important regulator of ENCC development. We find TNC dynamically expressed during avian gut development. It is absent from the cecal region just prior to ENCC arrival, but becomes strongly expressed around ENCCs as they enter the ceca and hindgut. In aganglionic hindguts, TNC expression is strong throughout the outer mesenchyme, but is absent from the submucosal region, supporting the presence of both ENCC-dependent and independent expression within the gut wall. Using rat-chick coelomic grafts, neural tube cultures, and gut explants, we show that ENCCs produce TNC and that this ECM protein promotes their migration. Interestingly, only vagal neural crest-derived ENCCs express TNC, whereas sacral neural crest-derived cells do not. These results demonstrate that vagal crest-derived ENCCs actively modify their microenvironment through TNC expression and thereby help to regulate their own migration.

A novel aspect of the structure of the avian thymic medulla

“…Both fibronectin and tenascin are capable of influencing cell migration (Savino et al 2000;2004). Various concentrations of tenascin can regulate neural crest cell migration (Akbareian et al 2013) and subsequently influence the effeciency of the autoreactive T-cell selection. The presence of reticular fibers at the corticomedullary border and in the inner medulla around the Hassall's bodies of human thymus has been shown by Yu and Lee (1993).…”

Tenascin-C at a glance

“…For example, tenascin-C promotes neural crest cell migration (Akbareian et al, 2013;Tucker, 2001), as well as migration of tumor cells and metastatic progression (Lowy and Oskarsson, 2015;Saupe et al, 2013). However, tenascin-C has also been shown to inhibit cell migration, especially in the case of growth cones (Faissner, 1997).…”

“…Another striking feature of tenascin-C is its tightly controlled gene expression pattern. In the embryo, tenascin-C is found around motile cells, at sites of epithelial-mesenchymal interactions and branching morphogenesis, and in dense connective tissue, such as bone, cartilage and tendons, as well as in the central nervous system (Akbareian et al, 2013;Sahlberg et al, 2001;Wiese and Faissner, 2015). However, little tenascin-C is found in the adult, where it is most prominent in stem cell niches and tendons (Chiquet-Ehrismann et al, 2014), and at sites of inflammation and trauma ; it is also particularly abundant in the stroma of solid tumors (Brösicke and Faissner, 2015;Lowy and Oskarsson, 2015;Midwood et al, 2011;Orend et al, 2014).…”

Building a second brain in the bowel

“…This seems unlikely, as migrating ENCDCs constantly change position, moving over each other (47,48). Another possibility is that ENCDCs enhance bowel colonization by altering ECM to enhance migration (65) or by degrading ECM to create spaces through which to migrate. Consistent with this latter hypothesis, MMP2 inhibition slows ENCDC migration (66).…”