Neural stem/progenitor cells (NSCs) proliferate and differentiate under tight regulation by various factors in the stem cell niche. Recent studies have shown that the precursor of nerve growth factor (NGF), proNGF, abounds in the central nervous system (CNS) and that its expression level in the brain is substantially elevated with aging as well as in several types of CNS disorders. In this study, we found for the first time that proNGF inhibited the proliferation of NSCs isolated from postnatal mouse hippocampus and caused cell cycle arrest in the G0/G1 phase without affecting apoptosis. In addition, proNGF reduced the differentiation of NSCs to oligodendrocytes. The effects of proNGF were blocked by the fusion protein of p75 neurotrophin receptor extracellular domain and human IgG Fc fragment (p75NTR/Fc), and by p75NTR knockout, suggesting that proNGF/p75NTR interaction was involved in the effects of proNGF on NSC proliferation and differentiation. proNGF decreased the phosphorylation level of extracellular signal responsive kinase 1/2 (ERK 1/2) in a p75NTR-dependent manner under both self-renewal and differentiation conditions. The inhibition of ERK 1/2 phosphorylation by U0126 significantly reduced the proliferation and oligodendrogenesis of NSCs, indicating that ERK 1/2 inhibition by proNGF partially explains its effects on NSC proliferation and oligodendrogenesis. These results suggest that the proNGF/p75NTR signal plays a key role in the regulation of NSCs' behavior.
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