PMID:21325529

Citation	Gadadhar, A, Marr, R and Lazarov, O (2011) Presenilin-1 regulates neural progenitor cell differentiation in the adult brain. J. Neurosci. 31:2615-23
Abstract	Presenilin-1 (PS1) is the catalytic core of the aspartyl protease γ-secretase. Previous genetic studies using germ-line deletion of PS1 and conditional knock-out mice demonstrated that PS1 plays an essential role in neuronal differentiation during neural development, but it remained unclear whether PS1 plays a similar role in neurogenesis in the adult brain. Here we show that neural progenitor cells infected with lentiviral vectors-expressing short interfering RNA (siRNA) for the exclusive knockdown of PS1 in the neurogenic microenvironments, exhibit a dramatic enhancement of cell differentiation. Infected cells differentiated into neurons, astrocytes and oligodendrocytes, suggesting that multipotentiality of neural progenitor cells is not affected by reduced levels of PS1. Neurosphere cultures treated with γ-secretase inhibitors exhibit a similar phenotype of enhanced cell differentiation, suggesting that PS1 function in neural progenitor cells is γ-secretase-dependent. Neurospheres infected with lentiviral vectors expressing siRNA for the targeting of PS1 differentiated even in the presence of the proliferation factors epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF), suggesting that PS1 dominates EFG and bFGF signaling pathways. Reduction of PS1 expression in neural progenitor cells was accompanied by a decrease in EGF receptor and β-catenin expression level, suggesting that they are downstream essential transducers of PS1 signaling in adult neural progenitor cells. These findings suggest a physiological role for PS1 in adult neurogenesis, and a potential target for the manipulation of neural progenitor cell differentiation.
Links	PubMed PMC3050597 Online version:10.1523/JNEUROSCI.4767-10.2011
Keywords	Adult Stem Cells/physiology; Analysis of Variance; Animals; Bromodeoxyuridine/metabolism; Carbamates/pharmacology; Cell Count; Cell Differentiation/genetics; Cells, Cultured; Cerebral Ventricles/cytology; Dipeptides/pharmacology; Down-Regulation/drug effects; Down-Regulation/genetics; Enzyme Inhibitors/pharmacology; Green Fluorescent Proteins/genetics; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neurogenesis/drug effects; Neurogenesis/genetics; Neurons/physiology; Presenilin-1/deficiency; Presenilin-1/metabolism; RNA, Small Interfering/genetics; RNA, Small Interfering/metabolism; Transfection/methods
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
MOUSE:PSN1		GO:0048666: neuron development	ECO:0000315:		P		Presenilin-1 (PSN1), mouse. Figure 3. Infection of neural progenitor by lentiviral vectors expressing PS1 1.1, and PS1 4.11 can give rise to the number of differentiated cells (neurons, astrocytes, and oligodendrocytes) without affecting their multipotentiality.	complete CACAO 12542

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