ATP DIFFERENTIALLY UPREGULATES FIBROBLAST GROWTH FACTOR 2 AND TRANSFORMING GROWTH FACTOR ALPHA IN NEONATAL AND ADULT MICE: EFFECT ON NEUROPROLIFERATION

作者：Jia C; Cussen A R; Hegg C C^*

来源：Neuroscience, 2011, 177: 335-346.

DOI：10.1016/j.neuroscience.2010.12.039

• purinergic receptor
• cell proliferation
• progenitor cell
• FGF2
• TGF alpha
• sustentacular cell

Multiple neurotrophic factors play a role in proliferation, differentiation and survival in the olfactory epithelium (OE); however, the signaling cascade has not been fully elucidated. We tested the hypotheses that ATP induces the synthesis and secretion of two neurotrophic factors, fibroblast growth factor 2 (FGF2) and transforming growth factor alpha (TGF alpha), and that these neurotrophic factors have a role in inducing proliferation. Protein levels of FGF2 and TGF alpha were increased 20 h post-intranasal instillation of ATP compared to vehicle control in adult Swiss Webster mice. Pre-intranasal treatment with purinergic receptor antagonist pyridoxal-phosphate-6-azophenyl-20,40-disulfonic acid (PPADS) significantly blocked this ATP-induced increase, indicating that upregulation of FGF2 and TGF alpha expression is mediated by purinergic receptor activation. However, in neonatal mouse, intranasal instillation of ATP significantly increased the protein levels of FGF2, but not TGF alpha. Likewise, ATP evoked the secretion of FGF2, but not TGF alpha, from neonatal mouse olfactory epithelial slices and PPADS significantly blocked ATP-evoked FGF2 release. To determine the role of FGF2 and TGF alpha in inducing proliferation, 5-bromo-2-deoxyuridine (BrdU) incorporation was examined in adult olfactory epithelium. Intranasal treatment with FGF receptor inhibitor PD173074 or epidermal growth factor receptor inhibitor AG1478 following ATP instillation significantly blocked ATP-induced BrdU incorporation. Collectively, these data demonstrate that ATP induces proliferation in adult mouse olfactory epithelium by promoting FGF2 and TGF alpha synthesis and activation of their receptors. These data suggest that different mechanisms regulate neurogenesis in neonatal and adult OE, and FGF2 and TGF alpha may have different roles throughout development.

• 出版日期2011-3-17