| Protein tyrosine phosphorylation, regulated by the opposing effects of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs), controls the growth and guidance of axons during development. This dissertation is dedicated to understanding action mechanisms employed by a cytosolic PTP called SHP-2 and a transmembrane PTP called PTPRO in the regulation of axon growth. By inhibiting SHP-2 activity in a transgenic mouse model, we examined the role of SHP-2 in sympathetic target innervation in vivo and in NGF-dependent neurite growth in vitro. Our results show that SHP-2 activity is required for appropriate sympathetic target innervation, and for NGF-induced neurite growth in cultured sympathetic neurons via positive regulation of the ERK signaling pathway. By screening for proteins interacting with the intracellular domain of PTPRO, we have identified a new class of proteins named “NPCD” (neuronal pentraxin with chromo domain). Our results indicate that NPCD proteins are selectively expressed in neurons, interact with PTPRO in vivo, and can serve as substrates for PTPRO. Using RNA interference, we show that NPCD is required for NGF-induced process outgrowth in PC12 cells. |
