Different pro-nerve growth factor protein variants elicit different biological outcome in PC12 cells

The nerve growth factor (NGF) is a neurotrophin produced as a precursor proNGF. Both proNGF and mature NGF (mNGF) are biologically active. mNGF, challenging the tropomyosin receptor A (TrkA) or to the p75 neurotrophin receptor (p75NTR)-TrkA complex, exerts neurotrophic effects. ProNGF can bind p75NRT/TrkA and/or the p75NRT-Sortilin complex, respectively eliciting neurotrophic and neurotoxic effects. We aimed to characterize the role of the two main murine proNGF variants, proNGF-A and proNGF-B, studying their biological effects on PC12 cells. To this aim, we first characterized the receptors phenotype of the PC12 cells, maintained in different culture conditions and then we studied the effect of proNGF variants on cell viability and differentiation. The presence of all of the possible mNGF/proNGF receptors on cell surface correlated with cell cycle phase and was promoted by serum starvation and/or by pretreatment with mNGF (priming). Both mNGF and proNGF-A promoted cell survival and differentiation in primed PC12 cells, while proNGF-B displayed neurotoxic properties. The neurotrophic effects of mNGF and proNGF-A were TrkA-dependent, while the blockade of p75NRT counteracted or even reverted the effects of proNGF-B. Our results suggest that proNGF-B and mNGF/proNGF-A preferentially challenge different receptor complexes, eliciting specific and opposite biological effects in PC12 cells.