Abstract
Neural stem cell (NSC) proliferation and differentiation play a pivotal role in the development of brain, the plasticity of the brain network, and the repair for brain function in CNS diseases. The mechanisms regulating NSC behavior are not well elucidated. Previous studies showed porf-2 functions as a modulator in central nerve system development. We here show that porf-2, a conserved family of RhoGAPs, is highly and specifically expressed in NSCs. We also demonstrate that porf-2 inhibits the proliferation of NSCs in vivo and in vitro, but has no effect on NSC differentiation. We investigated which domain is required for the role of porf-2 on NSC proliferation. By using neurosphere formation and Edu assay we confirmed the GAP domain is necessary for its function. In addition, we surveyed a few classical pathways on NSC proliferation and found that porf-2 inhibits NSC proliferation by suppressing the β-catenin nuclear translocation. Taken together, we show for the first time that porf-2 inhibits NSC proliferation through Wnt/β-catenin pathway by its GAP domain.
Highlights
In adult central nervous system (CNS), neural stem cell (NSC) proliferation and differentiation play a pivotal role in the development of brain, the plasticity of the brain network, and the repair for brain function in CNS diseases (Kempermann and Gage, 1999; Snyder et al, 2001; Koehl and Abrous, 2011; Mongiat and Schinder, 2011; Marin-Burgin and Schinder, 2012; Varela-Nallar and Inestrosa, 2013; Bond et al, 2015)
We show for the first time that porf-2, a conserved family of RhoGAPs, inhibits NSC proliferation through wnt/β-catenin pathway by its GTPase activating proteins (GAP) domain
After centrifugation at 500 g for 5 min at room temperature (RT) and removal of the supernatant, the cell pellets were resuspended in 1 ml of complete NSCs medium, DMEM/F12 (1:1) medium supplemented with 1 × B27 (Gibco, 17504), 1 × N2(Gibco, 17502-048), plus 100 U/ml penicillin, 100 μg/ml streptomycin (Gibco, 15140-122), and basic fibroblast growth factor (20 ng/ml, R&D), epidermal growth factor (EGF; 20 ng/ml, R&D)
Summary
In adult central nervous system (CNS), neural stem cell (NSC) proliferation and differentiation play a pivotal role in the development of brain, the plasticity of the brain network, and the repair for brain function in CNS diseases (Kempermann and Gage, 1999; Snyder et al, 2001; Koehl and Abrous, 2011; Mongiat and Schinder, 2011; Marin-Burgin and Schinder, 2012; Varela-Nallar and Inestrosa, 2013; Bond et al, 2015). NSCs develop into proliferating intermediate progenitor cells and the undifferentiated neuroblasts that will maturate into neurons, astrocytes or oligodendrocytes (Reynolds and Weiss, 1992; McKay, 1997; Gage, 2000; Zhao et al, 2006; Ming and Song, 2011). NSC transplantation is a promising therapeutic strategy in several CNS diseases, including brain and spinal cord injuries, stroke, epilepsy, and neurodegenerative disease
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