Wnt/beta-catenin signalling is dispensable for adult neural stem cell homeostasis and activation

Abstract

Adult mouse hippocampal neural stem cells (NSCs) generate new neurons that integrate into existing hippocampal networks and modulate mood and memory. These NSCs are largely quiescent and are stimulated by niche signals to activate and produce neurons. Wnt/β-catenin signalling acts at different steps along the hippocampal neurogenic lineage and has been shown to promote the proliferation of intermediate progenitor cells. However, whether it has a direct role in the regulation of NSCs still remains unclear. Here we used Wnt/β-catenin reporters and transcriptomic data from in vivo and in vitro models to show that both active and quiescent adult NSCs respond to Wnt/β-catenin signalling. Wnt/β-catenin stimulation instructed neuronal differentiation of active NSCs and promoted the activation or differentiation of quiescent NSCs in a dose-dependent manner. However, we found that inhibiting NSCs response to Wnt, by conditionally deleting β-catenin, did not affect their activation or maintenance of their stem cell characteristics. Together, our results indicate that whilst NSCs do respond to Wnt/β-catenin stimulation in a dose-dependent and state-specific manner, Wnt/β-catenin signalling is not cell-autonomously required to maintain NSC homeostasis, which could reconcile some of the contradictions in the literature as to the role of Wnt/β-catenin signalling in adult hippocampal NSCs.

Adult neural stem cells and neurogenesis are resilient to intermittent fasting

“…The appropriate sample size was based on previous publications studying NSC behaviour (Andersen 2014, Urban 2016, Blomfield 2019, Austin 2021), accounting for the increased variability of dietary interventions compared to genetic ones and considering female and male mice as separate groups. For the quantifications based on the YFP reporter, samples with a recombination rate lower than 80% were excluded.…”

“…Another particularity of our study is that the GlastCreER T2 ;RYFP mice we used had a mixed genetic background (Austin et al, 2020), while previous studies had used mice from the C57BL/6J strain. Strain-specific differences in the response of adult neurogenesis to dietary interventions such as high-fat diet have been reported (Hwang et al, 2008).…”