NT-3-mediated TrkC receptor activation promotes proliferation and cell survival of rodent progenitor oligodendrocyte cells in vitro and in vivo

Abstract

We have previously described the expression of a functional full-length trkC transcript for neurotrophin-3 (NT-3) receptor in oligodendroglia (OL) cells (Kumar and de Vellis, 1996). To date, the role of NT-3 and its signal transduction cascade in OL remains poorly defined. We report that the NT-3 responsive population of cells in the OL lineage are the progenitor cells and that the addition of NT-3 results in the autophosphorylation of p145TrkC. Furthermore, NT-3-mediated activation of p21ras and mitogen-activated protein kinase (MAPK), extracellular signal-regulated protein kinase2 (ERK2), were also observed in the progenitor OL cells. These protein tyrosine kinase (PTK)-induced responses were sensitive to the presence of K252a, an inhibitor for tyrosine kinase. We have determined that NT-3 promotes progenitor OL cell commitment to enter into S-phase of cell cycle to initiate DNA synthesis, in a manner similar to platelet-derived growth factor-AA (PDGF-AA). NT-3 thus plays a role in cell proliferation when present alone, while augmenting the proliferation capacity of PDGF-AA as indicated by the nuclear binding activity of the transcription factor, E2F-1. Both the initiation and progression of mitotic events were confirmed by the expression of c-myc and cdc2 in the presence of NT-3, PDGF-AA or NT-3 plus PDGF-AA. A cell survival assay examining interleukin 1-beta-converting enzyme (ICE)-like protease-mediated cleavage of poly (ADP-ribose) polymerase (PARP) revealed an increase in OL progenitor cell death in the absence of NT-3 or PDGF-AA. In corroboration with our in vitro studies, in vivo results show an increased expression of the progenitor OL cell marker, glycerol phosphate dehydrogenase (GPDH) within 48 hr following an intracranial injection of NT-3, PDGF-AA, or NT-3 plus PDGF-AA in PN4-5 rats. These novel findings suggest that PDGF-AA potentiates the OL progenitor cell's ability to enter into the S-phase of the cell cycle and that NT-3 can augment this activity. Furthermore, PDGF-AA and NT-3 can block ICE-like protease-mediated PARP fragmentation in progenitor OL cells. These results provide important information which further delineates the signal transduction cascades and the role of NT-3 and PDGF-AA on OL progenitor cells.

Multiplex proteomic analysis by two‐dimensional differential in‐gel electrophoresis

“…GPDH is a metabolic enzyme that catalyzes the conversion of dihydroxyacetone phosphate to glycerol-3-phosphate, providing phospholipid precursors for lipid biosynthesis and energy metabolism. Consistent with the above findings, GPDH might participate in different neuroprotective processes such as oligodendrocyte proliferation and survival [22]. Expression of GPDH in the brain has also been shown to increase dramatically during the active period of myelination, and is regulated by extracellular signals [23].…”

TrkC signaling is activated in adenoid cystic carcinoma and requires NT-3 to stimulate invasive behavior

“…Our interest in TrkC was further stimulated by its overexpression in cancers (for example, neuroblastoma, 4 melanoma, 5 and breast cancer 6 ), trophic stimulation by NT-3 and by the availability of small-molecule Trk inhibitors. 7 Trk receptors and neurotrophins are involved in almost all stages of nervous system development [8][9][10][11] where TrkC conveys NT-3-dependent pro-survival effects but triggers apoptosis in the absence of ligand. 12 Inactivating mutations in TrkC/NTRK3 have been recently associated with Hirschsprung disease, a developmental disorder characterized by the absence of ganglion cells in the myenteric and submucosal plexuses likely due to neural crest neuroblast migration defects.…”

Functional Recovery in Traumatic Spinal Cord Injury after Transplantation of Multineurotrophin-Expressing Glial-Restricted Precursor Cells

“…They are also important mediators of myelination. Mice lacking functional trkC or NT3 are deficient in both mature oligodendrocytes and OPCs (Kumar et al, 1998). NT3 enhances the survival and proliferation of OPCs in vitro Kumar et al, 1998;Yan and Wood, 2000;Franklin et al, 2001) and in vivo .…”

“…Mice lacking functional trkC or NT3 are deficient in both mature oligodendrocytes and OPCs (Kumar et al, 1998). NT3 enhances the survival and proliferation of OPCs in vitro Kumar et al, 1998;Yan and Wood, 2000;Franklin et al, 2001) and in vivo . Myelination by oligodendrocytes is also enhanced by NT3 in both cultures of neurons and the injured CNS (McTigue et al, 1998;Yan and Wood, 2000;Jean et al, 2003).…”