Loss of Dickkopf-1 Restores Neurogenesis in Old Age and Counteracts Cognitive Decline

Abstract

Memory impairment has been associated with age-related decline in adult hippocampal neurogenesis. Although Notch, bone morphogenetic protein, and Wnt signaling pathways are known to regulate multiple aspects of adult neural stem cell function, the molecular basis of declining neurogenesis in the aging hippocampus remains unknown. Here, we show that expression of the Wnt antagonist Dickkopf-1 (Dkk1) increases with age and that its loss enhances neurogenesis in the hippocampus. Neural progenitors with inducible loss of Dkk1 increase their Wnt activity, which leads to enhanced self-renewal and increased generation of immature neurons. This Wnt-expanded progeny subsequently matures into glutamatergic granule neurons with increased dendritic complexity. As a result, mice deficient in Dkk1 exhibit enhanced spatial working memory and memory consolidation and also show improvements in affective behavior. Taken together, our findings show that upregulating Wnt signaling by reducing Dkk1 expression can counteract age-related decrease in neurogenesis and its associated cognitive decline.

Hypothalamic radial glia function as self-renewing neural progenitors in the absence of Wnt/ß-catenin signaling

“…We found that a specific subset of lef1-dependent neurons located near the hypothalamic ventricle arise from the radial glial lineage . Combined with other studies in the retina (Agathocleous et al, 2009), cerebral cortex (Munji et al, 2011;Zhang et al, 2014), hippocampus (Seib et al, 2013) and midbrain (Castelo-Branco et al, 2003), our data suggest that the most widely conserved role for Wnt/β-catenin signaling in the CNS might be to regulate the differentiation of specific subsets of committed neural progenitors.…”

Kremen1 and Dickkopf1 control cell survival in a Wnt-independent manner

“…Interestingly, in the hippocampus of adult mice, conditional tamoxifen-induced loss of Dkk1 was shown to result in an increased apoptosis that specifically affects DCX + neuroblasts, 36 supporting the hypothesis that Dkk1 can act as a survival factor in physiological conditions.…”

Adding a spatial dimension to postnatal ventricular-subventricular zone neurogenesis

“…In the hippocampal subgranular zone, where the majority of temporal gene expression profiling studies have been performed, gene expression signatures were shown to be upregulated during aging. For example, antagonists of the Wnt signaling pathway are highly upregulated with aging and their ablation reverses the agerelated decline in neurogenesis (Seib et al, 2013). In the case of the V-SVZ, microdissection of defined microdomains followed by RNA or protein extraction can be performed to study the differential expression of TFs and/or the activity of signaling pathways (Azim et al, 2014b(Azim et al, , 2015 (Fig.…”