Insulin-like growth factor-I receptor and estrogen receptor crosstalk mediates hormone-induced neurite outgrowth in PC12 cells.
Estradiol (E(2)) and insulin-like growth factor-I (IGF-I) can act independently or in concert to promote neurite outgrowth in vivo and in cultured neurons. This study examined the role of crosstalk between estrogen receptor (ER)alpha and the IGF-I receptor as a critical mediator of hormone- and growth factor-dependent neurite outgrowth in a homogenous cell system. We used control PC12 cells and PC12 cells stably transfected with ER alpha, both of which express IGF-I receptor. Cells were treated for 1 week with vehicle, 1 nM E(2) or 100 ng/ml IGF-I alone or with E(2) or IGF-I in the presence of either the IGF-I receptor antagonist JB1 or the ER antagonist ICI 182,780. IGF-I significantly increased neurite outgrowth, as measured by the percentage of process-bearing cells, and absolute neurite length per cell in both control and ER alpha-transfected PC12 cells. In contrast, E(2) increased process formation and extension only in PC12 cells that were stably transfected with ER alpha. ICI 182,780 and JB1 blocked the IGF-I-induced increases in neurite length in both cell types. The efficacy of ICI 182,780 in control PC12 cells may have been due to the upregulation of ER alpha in these cells by the 7-day treatment with IGF-I. The ER and IGF-I receptor antagonists similarly blocked the E(2)-induced increase in neurite lengths in ER alpha-transfected cells. Immunofluorescent analysis of the cellular distribution of an axonal marker, phospho-neurofilament, verified that the processes extended by PC12 cells were neurites. These data suggest that receptor crosstalk between IGF-I receptors and ER alpha has an important role in neurite formation and extension even in a single-cell system.
Topalli
Ilir
I
Department of Neuroscience, Forchheimer 113, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Etgen
Anne M
AM
D000818:Animals; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D020847:Estrogen Receptor Modulators / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D000077267:Fulvestrant; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D016501:Neurites / Q000187:drug effects / Q000378:metabolism*; D016900:Neurofilament Proteins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000648:ultrastructure; D016716:PC12 Cells; D010641:Phenotype; D051381:Rats; D020239:Receptor Cross-Talk / Q000187:drug effects / Q000502:physiology*; D017526:Receptor, IGF Type 1 / Q000378:metabolism*
D020847:Estrogen Receptor Modulators; D047628:Estrogen Receptor alpha; D016900:Neurofilament Proteins; D000077267:Fulvestrant; D004958:Estradiol; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1