Wnt signalling regulates adult hippocampal neurogenesis

Abstract

The generation of new neurons from neural stem cells is restricted to two regions of the adult mammalian central nervous system: the subventricular zone of the lateral ventricle, and the subgranular zone of the hippocampal dentate gyrus. In both regions, signals provided by the microenvironment regulate the maintenance, proliferation and neuronal fate commitment of the local stem cell population. The identity of these signals is largely unknown. Here we show that adult hippocampal stem/progenitor cells (AHPs) express receptors and signalling components for Wnt proteins, which are key regulators of neural stem cell behaviour in embryonic development. We also show that the Wnt/beta-catenin pathway is active and that Wnt3 is expressed in the hippocampal neurogenic niche. Overexpression of Wnt3 is sufficient to increase neurogenesis from AHPs in vitro and in vivo. By contrast, blockade of Wnt signalling reduces neurogenesis from AHPs in vitro and abolishes neurogenesis almost completely in vivo. Our data show that Wnt signalling is a principal regulator of adult hippocampal neurogenesis and provide evidence that Wnt proteins have a role in adult hippocampal function.

Canonical and noncanonical Wnt signaling in neural stem/progenitor cells

“…Wnt-1 KO Altered central and peripheral neuronal development during initial axonogenesis [54] Wnt-1 KO Impaired midbrain development [55] Wnt-1 dominant negative Impaired hippocampal neurogenesis and spatial and object recognition memory [56,57] Wnt-1 overexpression Reduced neural differentiation of mESCs (also by treatment with lithium chloride) [58] Wnt-1 KO Increased differentiation into DA neurons in KO mESCs [59] Wnt-2 KO Decreased progenitor proliferation and neurogenesis in the ventral midbrain [60] Wnt-2 overexpression Induced dendritic arborization in hippocampal progenitors [61] Wnt-3 overexpression Increased differentiation of cortical intermediate [43] progenitors Wnt-3 overexpression Induced differentiation through cleavage of RYK in cortical progenitors [62] Wnt-3a KO Loss of the hippocampus [42] Recombinant Wnt-3a Induced GABAergic neuronal differentiation through RYK, reduced oligodendrogenesis [63] Recombinant Wnt-3a Induced differentiation of hESCs [64] Recombinant/purified Wnt-3a…”

Meningiomas exhibit loss of heterozygosity of the APC gene

“…New knowledge on wnt signaling shows that wnt proteins and other components of the wnt signaling cascade, like beta-catenin and axin regulate critical developmental processes of normal CNS development [13][14][15][16]. Although APC has been thought of primarily as a colonspecific tumor suppressor gene, its high expression in the CNS [17] and its critical involvement in particular syndromes, like the Tourcot syndrome [18], which includes the development of primary brain tumors such as medulloblastomas and gliomas [19], suggests that it performs important functions in these tissues also.…”

Neural stem cell- and neurogenesis-related gene expression profiles in the young and aged dentate gyrus

“…However, the extent of neurogenesis progressively declines with age resulting in~90 % decline in old age (Kuhn et al 1996;Rao et al 2005Rao et al , 2006. As old age is also associated with decreased ability for hippocampaldependent learning and memory function and increased incidence of depression, there is a widespread interest to understand the mechanisms underlying the age-related decrease in neurogenesis and to develop strategies that increase neurogenesis in the aged hippocampus (Bachstetter et al 2008;Bernal and Peterson 2004;Lie et al 2005;Drapeau and Abrous 2008;Hattiangady et al 2007;Jessberger and Gage 2008;Miranda et al 2012).…”