Abstract
A single asymmetric division by an adult neural stem cell (NSC) ultimately generates dozens of differentiated progeny, a feat made possible by the proliferative expansion of transit-amplifying progenitor cells (TAPs). Although NSC activation and TAP expansion is determined by pro- and anti-proliferative signals found within the niche, remarkably little is known about how these cells integrate simultaneous conflicting signals. We investigated this question focusing on the subventricular zone (SVZ) niche of the adult murine forebrain. Using primary cultures of SVZ cells, we demonstrate that Epidermal Growth Factor (EGF) and Bone Morphogenetic Protein (BMP)-2 are particularly powerful pro- and anti-proliferative factors for SVZ-derived neural precursors. Dose-response experiments showed that when simultaneously exposed to both signals, BMP dominantly suppressed EGF-induced proliferation; moreover, this dominance extended to all parameters of neural precursor behavior tested, including inhibition of proliferation, modulation of cell cycle, promotion of differentiation, and increase of cell death. BMP's anti-proliferative effect did not involve inhibition of mTORC1 or ERK signaling, key mediators of EGF-induced proliferation, and had distinct stage-specific consequences, promoting TAP differentiation but NSC quiescence. In line with these in vitro data, in vivo experiments showed that exogenous BMP limits EGF-induced proliferation of TAPs while inhibition of BMP-SMAD signaling promotes activation of quiescent NSCs. These findings clarify the stage-specific effects of BMPs on SVZ neural precursors, and support a hierarchical model in which the anti-proliferative effects of BMP dominate over EGF proliferation signaling to constitutively drive TAP differentiation and NSC quiescence.
Highlights
Neural stem cells (NSCs) are essential for the normal function, maintenance, and injury-induced repair of the adult central nervous system (CNS)
EGF family members signal through the Epidermal Growth Factor Receptor (EGFR), a cell surface tyrosine kinase receptor expressed in activated NSCs (Doetsch et al, 2002; Pastrana et al, 2009; Codega et al, 2014) and in the highly proliferative transit-amplifying progenitor cells (TAPs) (Sun et al, 2005; Ferron et al, 2011)
Our findings reveal a hierarchical relationship between two key niche signals, EGFR ligands and Bone Morphogenetic Protein (BMP), in regulating the quiescence/ proliferation/differentiation decisions of subventricular zone (SVZ) neural precursors
Summary
Neural stem cells (NSCs) are essential for the normal function, maintenance, and injury-induced repair of the adult central nervous system (CNS). Since SVZ NSCs are typically quiescent, re-entering the cell cycle only once every 2–3 weeks (Morshead et al, 1994), NSC roles in CNS homeostasis and repair are critically dependent on both NSC activation and, importantly, the proliferative expansion of their downstream TAPs. Proliferation of NSCs and TAPs (collectively referred to as neural precursors) is promoted by many families of molecules within the SVZ niche (Gage, 2000; Alvarez-Buylla and Lim, 2004; Pathania et al, 2010; Bond et al, 2012), including the Epidermal Growth Factor (EGF) family. Ligand-induced activation of EGFR stimulates proliferation of activated NSCs and TAPs in vivo and allows neural precursor expansion as neurospheres in vitro (Reynolds and Weiss, 1992; Craig et al, 1996; Paliouras et al, 2012). EGF treatment of cultured neural precursors stimulates mTOR activation within minutes, and EGF-induced mTOR activation is essential for proliferative expansion of the NSC lineage both in vitro and in vivo (Feliciano et al, 2011; Magri et al, 2011; Paliouras et al, 2012; Hartman et al, 2013)
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