APPL2 could inhibit neuronal differentiation but promote astrocytic differentiation via regulating Notch signaling in olfactory bulb

Abstract

PROBLEM: The continuous integration of newborn neurons in olfactory bulb (OB) is important for the odor sensory of mammalians during the lifetime. Neural stem cells (NSCs) in the subventricular zone (SVZ) generate neuroblasts that migrate along the rostral migratory stream (RMS) and integrate into OB circuitry. The molecular signals governing NSCs differentiation still remain undefined. BACKGROUND: Adaptor protein, phosphotyrosine interaction, PH domain and leucine zipper containing 2 (APPL2) is an important cellular signaling involved in the regulation of cellular metabolisms but the roles of APPL2 in regulating neurogenesis is unknown yet. HYPOTHESIS: We hypothesized that APPL2 might also participate in the regulating progress of neural stem cell differentiation during adult neurogenesis. RESEARCH: We conducted experiments to compare the difference between wild type mice and APPL2 transgenic mice in the neurogenesis in different brain area. By using different biomarkers, we identified the neuronal differentiation and astrocyte differentiation in the different brain area of wild type and APPL2 transgenic mice. OBSERVATIONS: We found that expression of APPL2 was increased during the process of induced NSCs differentiation in vitro. Overexpression of APPL2 oriented NSC into more astrocytes while knockdown of APPL2 enhanced neuronal differentiation in cultured NSCs. Furthermore, we found more numbers of GFAP+ cells in the Corpus callosum (CC) while fewer newborn neurons in OB of APPL2 transgenic mice than that of wild type mice. As a result of suppressed adult neurogenesis in OB, adult APPL2 transgenic mice (Tg) perform less sensitive in the olfactory discrimination tests (ODT) compared with wild type (WT) mice. Moreover, APPL2 can modulate Notch1 signaling pathway in cultured NSCs. CONCLUSIONS: The results reveal a new role of APPL2 in the regulating differentiation of NSCs into postnatal born neurons in SVZ-OB axis, thus strongly suggest potential importance of APPL2 in neurogenesis through regulating Notch1 signaling.