Wnt5a promotes differentiation and development of adult-born neurons in the hippocampus by noncanonical Wnt signaling

Abstract

In the adult hippocampus, new neurons are generated in the dentate gyrus. The Wnt signaling pathway regulates this process, but little is known about the endogenous Wnt ligands involved. We investigated the role of Wnt5a on adult hippocampal neurogenesis. Wnt5a regulates neuronal morphogenesis during embryonic development, and maintains dendritic architecture of pyramidal neurons in the adult hippocampus. Here, we determined that Wnt5a knockdown in the mouse dentate gyrus by lentivirus‐mediated shRNA impaired neuronal differentiation of progenitor cells, and reduced dendritic development of adult‐born neurons. In cultured adult hippocampal progenitors (AHPs), Wnt5a knockdown reduced neuronal differentiation and morphological development of AHP‐derived neurons, whereas treatment with Wnt5a had the opposite effect. Interestingly, no changes in astrocytic differentiation were observed in vivo or in vitro, suggesting that Wnt5a does not affect fate‐commitment. By using specific inhibitors, we determined that Wnt5a signals through CaMKII to induce neurogenesis, and promotes dendritic development of newborn neurons through activating Wnt/JNK and Wnt/CaMKII signaling. Our results indicate Wnt5a as a niche factor in the adult hippocampus that promotes neuronal differentiation and development through activation of noncanonical Wnt signaling pathways.

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

“…In addition, impaired dendritic arborization of newborn neurons was observed when knocking down Wnt5a. A similar effect was observed when Wnt5a was reduced in cultured AHPs, in which neuronal differentiation and morphological development of the derived neurons were reduced, while treatment with Wnt5a had the opposite effect (Arredondo et al, 2020). In agreement, chronic infusion of Wnt5a ligand into the adult rat hippocampus increased the number of immature neurons and altered their pattern of neurite outgrowth (Ortiz-Matamoros and Arias, 2019).…”

“…More recently, Wnt5a was also identified as an endogenous niche factor that regulates hippocampal neurogenesis. We determined that reducing the levels of Wnt5a in the dentate gyrus of adult mice decreased the generation of new neurons (Arredondo et al, 2020). Lentivirus-mediated knockdown of Wnt5a reduced the differentiation of neuronal committed progenitor cells, which remained as non-proliferative intermediate Sox2-expressing progenitors that failed to continue with the neuronal differentiation program.…”

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

“…Why canonical Wnt-signaling activity has to be downregulated during early phases of neurogenesis remains to be determined. Given the evidence for crosstalk and functional antagonism between different Wnt-pathways (Baksh, Boland et al, 2007, Mentink, Rella et al, 2018, we speculate that sustained -catenin-signaling interferes with noncanonical Wnt-signaling pathways and their essential function in dendrite patterning and growth (Arredondo et al, 2019, Goncalves et al, 2016a, Schafer et al, 2015.…”

“…Wnt proteins are key regulators of adult hippocampal neurogenesis (Arredondo, Guerrero et al, 2019, Jang, Bonaguidi et al, 2013, Lie, Colamarino et al, 2005, Qu, Sun et al, 2010, Qu, Sun et al, 2013, Seib, Corsini et al, 2013. Current data indicate that Wnts control different stages of adult neurogenesis via distinct pathways: while early developmental steps such as proliferation and fate determination of precursors are regulated by canonical Wnt/-catenin-4 signaling (Karalay, Doberauer et al, 2011, Kuwabara, Hsieh et al, 2009, Lie et al, 2005, Qu et al, 2013, late developmental steps such as neuronal maturation and morphogenesis are thought to be primarily regulated by non-canonical Wnt-signaling pathways (Arredondo et al, 2019, Schafer, Han et al, 2015. Supporting a sequential action of distinct Wnt-pathways is the finding that early adult-born neuron development and the initiation of neuronal morphogenesis are accompanied by the attenuation of canonical Wnt/-catenin-signaling activity and the increased activity of the non-canonical Wnt/planar cell polarity (PCP) signaling pathway (Schafer et al, 2015).…”

Intergenerational neurocognitive effects of intrauterine hyperglycemia on male offspring

“…Dopamine receptor Drd1 agonist could result in Camk2 activation, glutamate receptor exocytosis, synaptic reorganization, and expression of early markers of hippocampal synaptic plasticity [33]. Wnt5a regulates neuronal morphogenesis during embryonic development, and maintains dendritic architecture of pyramidal neurons in the adult hippocampus, through activating Wnt/JNK and Wnt/Camk2 signaling [34,35]. As a core protein involved in neurogenic Wnt signaling pathways, Atp6ap2 is critical for proliferating adult neural stem cells and differentiating neuroblasts, essential in early brain development, adult hippocampal neurogenesis and in cognitive functions.…”