Investigation of the function and potential crosstalk of ELK-1 and PEA3 proteins in neurons

PEA3 and ELK-1 transcription factor, members of the widely-known ETS superfamily, play role in various cellular processes. Elk-1 transcription factor is vital for cells due to regulates cell survival by regulating specific target genes in neurons. Pea3 proteins, consisting of Pea3, Erm, and Er81, are expressed in different tissues exhibiting branching, play a role in a variety of events such as formation of motor neuronal circuits in the nervous system, retinal differentiation, axon elongation. In the current study, we showed that Pea3 protein could promote neurite extension and axonal outgrowth in NSC-34 cells, and that phosphorylation sites such as Serine 90 and 285 are important for this function. We have also identified neurofilament-L and neurofilament-M as novel targets for Pea3 transcription factors. Other potential target genes have been identified in silico and microarray-based work in Pea3-VP16 overexpressed SH-SY5Y cells. Our microarray results indicated that Pea3 could regulate the expression of LTP-related genes, such as Mapk3, Prkcb and Ntrk3, as well as many other genes in axon guidance and neurotrophin signaling pathways. To explore LTP-related targets, we investigated Pea3, Erm, and Er81 expression and localization in the hippocampus as well as the possible regulation of these genes and of target genes in relation to neuronal activation and plasticity with Dr. Serge Laroche and his team at Paris Saclay Neuroscience Institute, University Paris-Sud. To investigate nervous system development and axon outgrowth related pathways, we have used qPCR, ChIP and other assays. Subsequently, we have also addressed target specificity of Pea3 family members Pea3, Erm, and Er81, particularly their overlapping vs specific target genes in neuronal differentiation in the nervous system using various model systems. And finally, we have shown that Elk-1 and Pea3 appear to cross-regulate each other and other ETS proteins, which we believe is to coordinate the transition from precursor proliferation to neuronal differentiation. All these studies contributed to our detailed understanding of the roles of Pea3 and Elk-1 proteins in the nervous system.