ERK-dependent and -independent pathways trigger human neural progenitor cell migration

• Published in: Toxicology and applied pharmacology Vol. 221; no. 1; pp. 57 - 67
• Main Authors: Moors, Michaela, Cline, Jason E., Abel, Josef, Fritsche, Ellen
• Format: Journal Article
• Language: English
• Published: San Diego, CA Elsevier Inc 15-05-2007; Elsevier
• Subjects: 60 APPLIED LIFE SCIENCES; ACETATES; APOPTOSIS; Astrocytes - cytology; Astrocytes - drug effects; Astrocytes - metabolism; Biological and medical sciences; Blotting, Western; BRAIN; Cell Differentiation - drug effects; Cell Movement - drug effects; Cell Movement - physiology; Cell Survival - drug effects; Cells, Cultured; EGFR; ERK1/2; ETHANOL; Flavonoids - pharmacology; GENE REGULATION; GROWTH FACTORS; HUMAN POPULATIONS; Humans; Indoles - pharmacology; Maleimides - pharmacology; Medical sciences; Methylmercury Compounds - pharmacology; Mitogen-Activated Protein Kinase 3 - antagonists & inhibitors; Mitogen-Activated Protein Kinase 3 - metabolism; Mitogen-Activated Protein Kinases - antagonists & inhibitors; Neural migration; Neurons - cytology; Neurons - drug effects; Neurons - metabolism; Normal human neural progenitor cells; PHOSPHORYLATION; Phosphorylation - drug effects; PHOSPHOTRANSFERASES; PKC; Protein Kinase C - antagonists & inhibitors; Protein Kinase C - metabolism; Pyrimidines - pharmacology; Quinazolines; RECEPTORS; Signal Transduction - drug effects; Signal Transduction - physiology; Spheroids, Cellular - cytology; Spheroids, Cellular - drug effects; Spheroids, Cellular - metabolism; src; src-Family Kinases - antagonists & inhibitors; src-Family Kinases - metabolism; Stem Cells - cytology; Stem Cells - drug effects; Stem Cells - metabolism; Sulfonamides - pharmacology; Tetradecanoylphorbol Acetate - pharmacology; Toxicology; Tyrphostins - pharmacology; PKC; ERK1/2; Neural migration; Normal human neural progenitor cells; src; EGFR; Human; Protein kinase C; Extracellular signal-regulated protein kinase; Enzyme; Transferases; Stem cell; Mitogen-activated protein kinase; Nervous system; Epidermal growth factor receptor; Cell motility; Extracellular signal-regulated protein kinase 2; Extracellular signal-regulated protein kinase 1; C-Onc gene; Protein-tyrosine kinase; Cell migration; Protooncogene; Progenitor cell
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2007.02.018

Besides differentiation and apoptosis, cell migration is a basic process in brain development in which neural cells migrate several centimeters within the developing brain before reaching their proper positions and forming the right connections. For identifying signaling events that control neural migration and are therefore potential targets of chemicals to disturb normal brain development, we developed a human neurosphere-based migration assay based on normal human neural progenitor (NHNP) cells, in which the distance is measured that cells wander over time. Applying this assay, we investigated the role of the extracellular signal-regulated kinases 1 and 2 (ERK1/2) in the regulation of NHNP cell migration. Exposure to model substances like ethanol or phorbol 12-myristate 13-acetate (PMA) revealed a correlation between ERK1/2 activation and cell migration. The participation of phospho-(P-) ERK1/2 was confirmed by exposure of the cells to the MEK inhibitor PD98059, which directly prohibits ERK1/2 phosphorylation and inhibited cell migration. We identified protein kinase C (PKC) and epidermal growth factor receptor (EGFR) as upstream signaling kinases governing ERK1/2 activation, thereby controlling NHNP cell migration. Additionally, treatments with src kinase inhibitors led to a diminished cell migration without affecting ERK1/2 phosphorylation. Based on these results, we postulate that migration of NHNP cells is controlled via ERK1/2-dependent and -independent pathways.