The effects of laminin-1 on spiral ganglion neurons are dependent on the MEK/ERK signaling pathway and are partially independent of Ras.
Laminin-1 (LN) is expressed along the route of neural growth from spiral ganglion (SG) neurons towards the developing organ of Corti, and has been shown to enhance neurite outgrowth from SG neurons in vitro. Signal transduction pathways linking LN signaling at the cell membrane to the cell nucleus can involve a variety of signaling molecules. Data from other systems suggest the potential involvement of the small G protein Ras, and the mitogen-activated protein kinases (MAPKs) Erk and/or p38. To assess these possibilities, the length and number of processes extending from SG explants cultured on LN-coated surfaces were evaluated after treatment with the Ras inhibitor FTI-277, the p38 inhibitor SB203580 and MAPK kinase (MEK) inhibitor U0126, which operates immediately upstream of the Erk MAPK. Treatment with the Ras inhibitor at levels known to inhibit the H- and N-Ras isoforms had no effect, while FTI-277 levels known to inhibit K-Ras reduced only neurite length. Suppression of MEK resulted in a decrease of both parameters, while incubation with the p38 inhibitor had no effect. The results of this study suggest that MEK plays a central role in LN signaling in SG neurites. While K-Ras signaling may participate in MEK-dependent increases in neurite length, the MEK-dependent increase in neurite number appears to be activated by a different intracellular pathway.
Aletsee
Christoph
C
Department of Surgery/Otolaryngology and Neurosciences, UCSD School of Medicine and VA Medical Center, 9500 Gilman Drive #0666, La Jolla, CA 92093, USA.
Brors
Dominik
D
Palacios
Sean
S
Pak
Kwang
K
Mullen
Lina
L
Dazert
Stefan
S
Ryan
Allen F
AF
D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D002478:Cells, Cultured; D007093:Imidazoles / Q000494:pharmacology; D007797:Laminin / Q000494:pharmacology*; D008715:Methionine / Q000031:analogs & derivatives* / Q000494:pharmacology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016501:Neurites / Q000187:drug effects / Q000648:ultrastructure; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D015398:Signal Transduction; D013136:Spiral Ganglion / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D018631:ras Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*
D002070:Butadienes; C096856:FTI 277; D007093:Imidazoles; D007797:Laminin; D009570:Nitriles; D011725:Pyridines; C113580:U 0126; C121346:laminin 1; D008715:Methionine; D020928:Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D018631:ras Proteins; C093642:SB 203580