Abstract
Inherited and acquired defects in neurogenesis contribute to neurodevelopmental disorders, dysfunctional neural plasticity, and may underlie pathology in a range of neurodegenerative conditions. Mitogen-activated protein kinases (MAPKs) regulate the proliferation, survival, and differentiation of neural stem cells. While the balance between MAPKs and the family of MAPK dual-specificity phosphatases (DUSPs) regulates axon branching and synaptic plasticity, the specific role that DUSPs play in neurogenesis remains unexplored. In the current study, we asked whether the canonical DUSP, MAP Kinase Phosphatase-1 (MKP-1), influences neural stem cell differentiation and the extent to which DUSP-dependent autophagy is operational in this context. Under basal conditions, Mkp-1 knockout mice generated fewer doublecortin (DCX) positive neurons within the dentate gyrus (DG) characterized by the accumulation of LC3 puncta. Analyses of wild-type neural stem cell (NSC) differentiation in vitro revealed increased Mkp-1 mRNA expression during the initial 24-h period. Notably, Mkp-1 KO NSC differentiation produced fewer Tuj1-positive neurons and was associated with increased expression of the BCL2/adenovirus E1B 19-kD protein-interacting protein 3 (BNIP3) and levels of autophagy. Conversely, Bnip3 knockdown in differentiated Mkp-1 KO NSCs reduced levels of autophagy and increased neuronal yields. These results indicate that MKP-1 exerts a pro-neurogenic bias during a critical window in NSC differentiation by regulating BNIP3 and basal autophagy levels.
Highlights
Neurogenesis is a tightly controlled process occurring during embryonic development that persists in the adult brain, primarily within the subventricular zone (SVZ) and the hippocampal dentate gyrus (DG)
To evaluate the potential influence that MAP Kinase Phosphatase-1 (MKP-1) has on neurogenesis, we first assessed whether loss of MKP-1 function altered the number of doublecortin (DCX) positive neurons within the dentate gyrus (DG)
We investigated the effect of differentiation on endogenous Mkp-1 mRNA expression using an in vitro model of neural stem cell differentiation cultures (NSC-D)
Summary
Neurogenesis is a tightly controlled process occurring during embryonic development that persists in the adult brain, primarily within the subventricular zone (SVZ) and the hippocampal dentate gyrus (DG). During the initial phase of CNS development, the brain generates up to 250,000 neurons per minute [1]. Adult hippocampal neurogenesis in the DG is highly conserved across mammals [2]. Under conditions of mild physiological stress, cell-intrinsic responses and the release of brain-derived neurotrophic factor (BDNF) induces neurogenesis [5]. Genetic conditions, such as Down Syndrome, and age-related neurodegenerative conditions, such as Parkinson’s and Alzheimer’s diseases, are associated with a net reduction in neural stem cell (NSC)
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