Turning Death to Growth: Hematopoietic Growth Factors Promote Neurite Outgrowth through MEK/ERK/p53 Pathway.

Stem cell factor (SCF) and granulocyte colony-stimulating factor (G-CSF) are the essential hematopoietic growth factors to control hematopoiesis. However, the role of SCF and G-CSF in the central nervous system remains poorly understood. Here, we have demonstrated the involvement of MEK/ERK/p53 signaling in SCF + G-CSF-enhanced neurite extension. Cortical neurons dissected from embryonic rat brains were seeded onto the membranes of transwell inserts, and neurite outgrowth was determined by using both the neurite outgrowth quantification assay kit and immunostaining of β III tubulin. Quantitative RT-PCR and western blotting were used for determining gene and protein expression of ERK and p53, respectively. p53 small interfering RNA (siRNAs) were introduced into neurons for examining the involvement of p53 in SCF + G-CSF-mediated neurite outgrowth. We observed that both SCF and G-CSF alone increased activation of MEK/ERK and gene expression of p53, while SCF + G-CSF synergistically activated the MEK/ERK signaling and upregulated p53 expression. MEK specific inhibitors (PD98059 and U0126) blocked the SCF + G-CSF-increased ERK phosphorylation and p53 gene and protein expression, and the MEK specific inhibitors also eliminated the SCF + G-CSF-promoted neurite outgrowth. p53 siRNAs knocked down the SCF + G-CSF-elevated p53 protein and prevented the SCF + G-CSF-enhanced neurite outgrowth. These findings suggest that activation of MEK/ERK/p53 signaling is required for SCF + G-CSF-promoted neurite outgrowth. Through the pro-apoptotic pathway of the MEK/ERK/p53, SCF + G-CSF turns neuronal fate from apoptotic commitment toward neural network generation. This observation provides novel insights into the putative role of SCF + G-CSF in supporting generation of neural connectivity during CNS development and in brain repair under pathological or neurodegenerative conditions.