Premium
NT3 inhibits FGF2‐induced neural progenitor cell proliferation via the PI3K/GSK3 pathway
Author(s) -
Jin Lu,
Hu Xinhua,
Feng Linyin
Publication year - 2005
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2005.03118.x
Subject(s) - progenitor cell , pi3k/akt/mtor pathway , neural stem cell , microbiology and biotechnology , progenitor , cell growth , neuroscience , chemistry , biology , signal transduction , stem cell , biochemistry
Neurotrophin 3 (NT3), a member of the neurotrophin family, antagonizes the proliferative effect of fibroblast growth factor 2 (FGF2) on cortical precursors. However, the mechanism by which NT3 inhibits FGF2‐induced neural progenitor (NP) cell proliferation is unclear. Here, using an FGF2‐dependent rat neurosphere culture system, we found that NT3 inhibits both FGF2‐induced neurosphere growth and bromodeoxyuridine (BrdU) incorporation in a dose‐dependent manner. U0126, a mitogen‐activated protein kinase kinase 1/2 (MEK1/2) inhibitor, and LY294002, a phosphatidylinositol 3‐kinase (PI3K) inhibitor, both inhibited FGF2‐induced BrdU incorporation, suggesting that the extracellular signal‐regulated kinase1/2 (ERK1/2) and PI3K pathways are required for FGF2‐induced NP cell proliferation. NT3 significantly inhibited FGF2‐induced phosphorylation of Akt and glycogen synthase kinase 3β (GSK3β), a downstream kinase of Akt, whereas phosphorylation of ERK1/2 was unaffected. The inhibitory effect of NT3 on FGF2‐induced NP cell proliferation was abolished by LY294002, and treatment with SB216763, a specific GSK3 inhibitor, antagonized the NT3 effect, rescuing both neurosphere growth and BrdU incorporation. Moreover, experiments with anti‐NT3 antibody revealed that endogenous NT3 also plays a role in inhibiting FGF2‐induced NP cell proliferation, and that anti‐NT3 antibody enhanced phospho‐Akt and phospho‐GSK3β levels in the presence of FGF2. These findings indicate that FGF2‐induced NP cell proliferation is inhibited by NT3 via the PI3K/GSK3 pathway.