Notch3 signaling gates cell cycle entry and limits neural stem cell amplification in the adult pallium

Abstract

SUMMARYMaintaining the homeostasis of germinal zones in adult organs is a fundamental but mechanistically poorly understood process. In particular, what controls stem cell activation remains unclear. We have previously shown that Notch signaling limits neural stem cell (NSC) proliferation in the adult zebrafish pallium. Combining pharmacological and genetic manipulations, we demonstrate here that long-term Notch invalidation primarily induces NSC amplification through their activation from quiescence and increased occurrence of symmetric divisions. Expression analyses, morpholino-mediated invalidation and the generation of a notch3-null mutant directly implicate Notch3 in these effects. By contrast, abrogation of notch1b function results in the generation of neurons at the expense of the activated NSC state. Together, our results support a differential involvement of Notch receptors along the successive steps of NSC recruitment. They implicate Notch3 at the top of this hierarchy to gate NSC activation and amplification, protecting the homeostasis of adult NSC reservoirs under physiological conditions.

Notch3 establishes brain vascular integrity by regulating pericyte number

“…To investigate functions of Notch3 signaling in pericyte development, we first examined embryos and larvae homozygous for a previously identified nonsense mutation of notch3 (Alunni et al, 2013). The notch3 fh332 allele is predicted to generate a nonfunctional truncated protein lacking the entire intracellular domain and half of the EGF repeats of the extracellular domain (Alunni et al, 2013).…”

“…The notch3 fh332 allele is predicted to generate a nonfunctional truncated protein lacking the entire intracellular domain and half of the EGF repeats of the extracellular domain (Alunni et al, 2013). Mutant larvae showed distinct trunk curvature at 3 days post fertilization (dpf), but otherwise appeared morphologically normal (supplementary material Fig.…”

“…Embryos were produced by pair matings and raised at 28.5°C in egg water or embryo medium and staged according to hpf or dpf. Strains in addition to new transgenic lines described below included AB, Tg(fli1a:EGFP) , Tg(Tp1bglob:hmgb1-mCherry) (Parsons et al, 2009) and notch3 fh332 (Alunni et al, 2013).…”

Notch maintains Drosophila type II neuroblasts by suppressing the expression of the Fez transcription factor Earmuff

“…Loss of Notch or its downstream components can lead to depletion of the NSC pool and precocious neuronal differentiation (de la Pompa et al, 1997;Grandbarbe et al, 2003;Hatakeyama et al, 2004;Ishibashi et al, 1995;Ohtsuka et al, 1999;Yun et al, 2002). Differences in Notch receptors, signaling strength and dynamics, and pathway components may contribute to NSC heterogeneity (Alunni et al, 2013;Basak et al, 2012;Ehm et al, 2010;Giachino and Taylor, 2014). However, the detailed mechanism of Notch-mediated maintenance of NSC self-renewal and heterogeneity is still not fully understood.…”

Cellules souches neurales et signalisation Notch

“…La signalisation Notch apparaît comme l'un des mécanismes essentiels de la régulation de l'équilibre entre le maintien et la diffé- [28]. Chez la souris, le ligand Dll1 exprimé dans les CSN activées est lui-même directement impliqué dans le maintien des CSN de la niche puisque, lors des divisions asymétriques, une seule des deux cellules filles est capable d'exprimer Dll1 et de se différencier, alors que l'autre reste indifférenciée et quiescente [29].…”