Interactions between fibroblast growth factors and Notch regulate neuronaldifferentiation

The differentiation of precursor cells into neurons has been shown to be in fluenced by both the Notch signaling pathway and growth factor stimulation. In this study, the regulation of neuronal differentiation by these mechani sms was examined in the embryonic day 10 neuroepithelial precursor (NEP) po pulation. By downregulating Notch1 expression and by the addition of a Delt a1 fusion protein (Delta Fc), it was shown that signaling via the Notch pat hway inhibited neuron differentiation in the NEP cells, in vitro. The expre ssion of two of the Notch receptor homologs, Notch1 and Notch3, and the lig and Delta1 in these NEP cells was found to be influenced by a number of dif ferent growth factors, indicating a potential interaction between growth fa ctors and Notch signaling. Interestingly, none of the growth factors examin ed promoted neuron differentiation; however, the fibroblast growth factors (FGFs) 1 and 2 potently inhibited differentiation. FGF1 and FGF2 upregulate d the expression of Notch and decreased expression of Delta1 in the NEP cel ls. In addition, the inhibitory response of the cells to the FGFs could be overcome by downregulating Notch1 expression and by disrupting Notch cleava ge and signaling by the ablation of the Presenilin1 gene. These results ind icate that FGF1 and FGF2 act via the Notch pathway, either directly or indi rectly, to inhibit differentiation. Thus, signaling through the Notch recep tor may be a common regulator of neuronal differentiation within the develo ping forebrain.