Canonical Wnt-signaling modulates the tempo of dendritic growth of adult-born hippocampal neurons

Abstract

In adult hippocampal neurogenesis neural stem/progenitor cells generate new dentate granule neurons that contribute to hippocampal plasticity. The establishment of a morphologically defined dendritic arbor is central to the functional integration of adult-born neurons. Here, we investigated the role of canonical Wnt/-catenin-signaling in dendritogenesis of adult-born neurons. We show that canonical Wnt-signaling follows a biphasic pattern, with high activity in stem/progenitor cells, attenuation in early immature neurons, and re-activation during maturation, and demonstrate that the biphasic activity pattern is required for proper dendrite development. Increasing -catenin-signaling in maturing neurons of young adult mice transiently accelerated dendritic growth, but eventually resulted in dendritic defects and excessive spine numbers. In middle-aged mice, in which protracted dendrite and spine development was paralleled by lower canonical Wnt-signaling activity, enhancement of catenin-signaling restored dendritic growth and spine formation to levels observed in young adult animals. Our data indicate that precise timing and strength of -catenin-signaling is essential for the correct functional integration of adult-born neurons and suggest Wnt/catenin-signaling as a pathway to ameliorate deficits in adult neurogenesis during aging.

Role of Wnt Signaling in Adult Hippocampal Neurogenesis in Health and Disease

“…Growing evidence suggest that the Wnt signaling pathway is part of the signaling mechanisms affected, that might contribute to the decline in neurogenesis (Figure 2). In support of this idea, β-catenin reporter mice exhibit a strong decrease in β-catenin signaling activity in the GCL with age, and increasing β-catenin activity counteracts the age-associated maturation defects of adult-born dentate granule neurons (Heppt et al, 2020). In addition, the expression of Wnt3 and Wnt3a in the dentate gyrus decreases with age, concomitantly with the decrease in newborn neurons positive for NeuroD1 (Okamoto et al, 2011).…”

“…Interestingly, β-catenin reporter mouse lines showed a peak of Wnt/β-catenin activity during early stages of adult hippocampal neurogenesis. Different transgenic reporter mouse lines have been used to evaluate the activity of Wnt/β-catenin signaling in the dentate gyrus: the BATGAL mice (Lie et al, 2005;Garbe and Ring, 2012;Heppt et al, 2020), the ins-topGal mice (Garbe and Ring, 2012), and the Axin2 LacZ/+ mice (Heppt et al, 2020). Although the expression pattern of the reporter activity is not exactly the same in the different mouse lines likely for the molecular construct of the transgenes, the use of BrdU birth-dating strategies and specific molecular markers together with the reporter activity showed that Wnt/β-catenin signaling is active during early stages of adult hippocampus neurogenesis (including NPCs and proliferating neuroblasts), and is attenuated in immature neurons (Lie et al, 2005;Garbe and Ring, 2012;Heppt et al, 2020).…”

“…Interestingly, Wnt/β-catenin activity is reactivated in mature newborn neurons (Garbe and Ring, 2012;Heppt et al, 2020), suggesting that the canonical Wnt pathway might also control later stages of neurogenesis such as maturation or synaptic integration. Notably, it was recently shown that the attenuation of Wnt/β-catenin signaling in early stages of newborn neurons is required for correct dendrite development, and Wnt/β-catenin reactivation in maturing neurons modulates the tempo of dendritic growth and spine formation (Heppt et al, 2020), indicating that a precise control of Wnt signaling activity is required for the generation of new granule cells in the adult hippocampus.…”

“…Different transgenic reporter mouse lines have been used to evaluate the activity of Wnt/β-catenin signaling in the dentate gyrus: the BATGAL mice ( Lie et al, 2005 ; Garbe and Ring, 2012 ; Heppt et al, 2020 ), the ins-topGal mice ( Garbe and Ring, 2012 ), and the Axin2 LacZ/+ mice ( Heppt et al, 2020 ). Although the expression pattern of the reporter activity is not exactly the same in the different mouse lines likely for the molecular construct of the transgenes, the use of BrdU birth-dating strategies and specific molecular markers together with the reporter activity showed that Wnt/β-catenin signaling is active during early stages of adult hippocampus neurogenesis (including NPCs and proliferating neuroblasts), and is attenuated in immature neurons ( Lie et al, 2005 ; Garbe and Ring, 2012 ; Heppt et al, 2020 ). Considering that activation of a specific Wnt signaling pathway may antagonize the activation of other Wnt signaling cascades ( Ishitani et al, 2003 ; Topol et al, 2003 ; Mikels and Nusse, 2006 ; Grumolato et al, 2010 ; Sato et al, 2010 ; Mentink et al, 2018 ), it is feasible to suggest that the Wnt/β-catenin pathway might be inhibited after fate commitment by the activation of non-canonical Wnt signaling cascades, which as discussed, regulate the development of newborn neurons ( Schafer et al, 2015 ; Arredondo et al, 2020 ).…”

“…Considering that activation of a specific Wnt signaling pathway may antagonize the activation of other Wnt signaling cascades ( Ishitani et al, 2003 ; Topol et al, 2003 ; Mikels and Nusse, 2006 ; Grumolato et al, 2010 ; Sato et al, 2010 ; Mentink et al, 2018 ), it is feasible to suggest that the Wnt/β-catenin pathway might be inhibited after fate commitment by the activation of non-canonical Wnt signaling cascades, which as discussed, regulate the development of newborn neurons ( Schafer et al, 2015 ; Arredondo et al, 2020 ). Interestingly, Wnt/β-catenin activity is reactivated in mature newborn neurons ( Garbe and Ring, 2012 ; Heppt et al, 2020 ), suggesting that the canonical Wnt pathway might also control later stages of neurogenesis such as maturation or synaptic integration. Notably, it was recently shown that the attenuation of Wnt/β-catenin signaling in early stages of newborn neurons is required for correct dendrite development, and Wnt/β-catenin reactivation in maturing neurons modulates the tempo of dendritic growth and spine formation ( Heppt et al, 2020 ), indicating that a precise control of Wnt signaling activity is required for the generation of new granule cells in the adult hippocampus.…”