The long-term research objective of this project is to understand the functions of both bHLH repressors and bHLH activators in neurotrophic growth factor signaling. Previous studies by this laboratory have shown that the mammalian homolog of the Drosophila Hairy and Enhancer of Split proteins, HES-1, acts as a repressor of neural differentiation in PC12 cells. Their work demonstrated that HES-1 is a nuclear target and effector of NGF signaling. In the current proposal, the investigators will extend their analysis of bHLH proteins in neurotrophic signaling by carrying out experiments aimed at studying the role of HES-1 in primary neuronal cultures derived from both the PNS and CNS. In addition, they plan to study the role of MASH-1, a bHLH activator, in mediating NGF signaling. The experimental goals for the proposed project are to test the following hypotheses: 1) HES-1 is a key mediator of NGF signaling in primary neurons from the PNS and CNS. 2) HES-1 also mediates the effect of other neurotrophic growth factors in H19-7 cells. 3) MASH-1 is an essential mediator that is necessary and sufficient for NGF-dependent neural differentiation to occur in PC12 cells. 4) MASH-1 is a functional target for HES-1 in PC12 cells.
