MT5-MMP regulates adult neural stem cell functional quiescence through the cleavage of N-cadherin

Abstract

The identification of mechanisms that maintain stem cell niche architecture and homeostasis is fundamental to our understanding of tissue renewal and repair. Cell adhesion is a well-characterized mechanism for developmental morphogenetic processes, but its contribution to the dynamic regulation of adult mammalian stem cell niches is still poorly defined. We show that N-cadherin-mediated anchorage of neural stem cells (NSCs) to ependymocytes in the adult murine subependymal zone modulates their quiescence. We further identify MT5-MMP as a membrane-type metalloproteinase responsible for the shedding of the N-cadherin ectodomain in this niche. MT5-MMP is co-expressed with N-cadherin in adult NSCs and ependymocytes and, whereas MT5-MMP-mediated cleavage of N-cadherin is dispensable for the regulation of NSC generation and identity, it is required for proper activation of NSCs under physiological and regenerative conditions. Our results indicate that the proliferative status of stem cells can be dynamically modulated by regulated cleavage of cell adhesion molecules.

Canonical and noncanonical Wnt signaling in neural stem/progenitor cells

“…Similar results were obtained in an unrelated study using Ncadherin mutant mice, where loss of N-cadherin reduced -catenin signaling and induced migration from the niche and differentiation [118]. An analogous situation was reported in the SVZ, where MT5-MMP was found to be the metalloproteinase that controls N-cadherin cleavage and subsequent activation of NSCs [119]. These reports highlight the potential importance of -catenin signaling in regulating cell interactions in the stem cell niche and linking them to proliferation and stemness.…”

N-cadherin-based adherens junction regulates the maintenance, proliferation, and differentiation of neural progenitor cells during development

“…MT5-MMP-mediated cleavage of N-cadherin is dispensable for the regulation of adult neural stem cell generation and identity. 81 However, the signals from ependymal cells and endothelial cells to maintain the niche are mostly unknown. The neural stem cells can renew themselves and generate transient amplifying (TA) cells by asymmetric division, and subsequently the TA cells generate neuroblast cells.…”

Prdm16 is required for the maintenance of neural stem cells in the postnatal forebrain and their differentiation into ependymal cells

“…These multipotent progenitors in turn give rise to neuroblasts and differentiated neurons (Lim and Alvarez-Buylla 2014). The SVZ also contains astrocytes, endothelial cells, and ependymal cells, each of which regulates neural stem cell function and neurogenesis (Lim et al 2000;Mirzadeh et al 2008;Porlan et al 2014). Ependymal cells are multiciliated cells that line the walls of the ventricles in the central nervous system (CNS) and promote the directional flow of cerebrospinal fluid (CSF) (Sawamoto et al 2006;Mirzadeh et al 2010b;Faubel et al 2016).…”