RESUMEN
Klotho is an aging-related protein associated with hippocampal cognitive performance in mammals. Klotho regulates progenitor cell proliferation in non-neuronal tissues, but its role in adult hippocampal neurogenesis (AHN) has not been explored. Klotho expression in the adult mouse hippocampus was examined by immunofluorescence and polymerase chain reaction. AHN was evaluated in the hippocampus of klotho knock-out mice (KO), klotho KO/vitamin D-receptor mutant mice, and in a model of local klotho hippocampal knockdown. The recombinant Klotho effect on proliferation was measured in mouse-derived hippocampal neural progenitor cells. Hippocampal-dependent memory was assessed by a dry-land version of the Morris water maze. Klotho was expressed in the granular cell layer of the adult Dentate Gyrus. AHN was increased in klotho KO mice, but not in klotho KO/vitamin D-receptor mutant mice. Inversely, local downregulation of hippocampal Klotho diminished AHN. Recombinant Klotho increased the proliferation rate of neural progenitors. Downregulation of hippocampal Klotho correlated with a decreased performance in hippocampal-dependent memory. These results suggest that Klotho directly participates in regulating AHN. Our observations indicate that Klotho promotes proliferation, AHN and hippocampal-dependent cognition. Increased neurogenesis in klotho KO mice may be secondary to the activation of other pathways altered in the model, such as vitamin D.
Asunto(s)
Proliferación Celular/fisiología , Giro Dentado , Glucuronidasa/metabolismo , Memoria/fisiología , Neurogénesis/fisiología , Animales , Conducta Animal/fisiología , Cognición/fisiología , Giro Dentado/diagnóstico por imagen , Giro Dentado/metabolismo , Técnica del Anticuerpo Fluorescente/métodos , Proteínas Klotho , Aprendizaje por Laberinto , Ratones , Células-Madre Neurales/fisiologíaRESUMEN
BACKGROUND: In the adult hippocampus new neurons are continuously generated from neural stem cells (NSCs) present at the subgranular zone of the dentate gyrus. This process is controlled by Wnt signaling, which plays a complex role in regulating multiple steps of neurogenesis including maintenance, proliferation and differentiation of progenitor cells and the development of newborn neurons. Differential effects of Wnt signaling during progression of neurogenesis could be mediated by cell-type specific expression of Wnt receptors. Here we studied the potential role of Frizzled-1 (FZD1) receptor in adult hippocampal neurogenesis. RESULTS: In the adult dentate gyrus, we determined that FZD1 is highly expressed in NSCs, neural progenitors and immature neurons. Accordingly, FZD1 is expressed in cultured adult hippocampal progenitors isolated from mouse brain. To evaluate the role of this receptor in vivo we targeted FZD1 in newborn cells using retroviral-mediated RNA interference. FZD1 knockdown resulted in a marked decrease in the differentiation of newborn cells into neurons and increased the generation of astrocytes, suggesting a regulatory role for the receptor in cell fate commitment. In addition, FZD1 knockdown induced an extended migration of adult-born neurons within the granule cell layer. However, no differences were observed in total dendritic length and dendritic arbor complexity between control and FZD1-deficient newborn neurons. CONCLUSIONS: Our results show that FZD1 regulates specific stages of adult hippocampal neurogenesis, being required for neuronal differentiation and positioning of newborn neurons into the granule cell layer, but not for morphological development of adult-born granule neurons.