LIM kinase mediates estrogen action on the actin depolymerization factor Cofilin.
The ovarian hormone estrogen increases the axospinous synapse density in the hippocampal CA1 region of young female rats but fails to do so in aged rats. This estrogen-mediated alteration of spine synapse structures suggests the coincident requirement for the structural reorganization of the underlying actin cytoskeleton network. Actin reorganization is known to require the deactivation of Cofilin, an actin depolymerization factor. Cofilin is deactivated by LIM kinase (LIMK), and LIMK activity is modulated by the phosphorylation of specific residues. We have previously demonstrated that estrogen is able to increase phosphorylated LIMK (pLIMK) immunoreactivity (IR) in the hippocampus in vivo and that this estrogen-stimulated pLIMK-IR is decreased in the aged brain. Because Cofilin phosphorylation allows for actin filament elongation and spine synapse growth, we sought to determine if estrogen acts through Cofilin and if such estrogen action requires the observed LIMK activity. Using both hippocampal neurons and the NG108-15 neuroblastoma cell line, we demonstrate here that estrogen stimulates the phosphorylation of Cofilin in vitro. Furthermore, this estrogen action on Cofilin requires LIMK. Lastly, while initiating the phosphorylation of LIMK and Cofilin, estrogen can also stimulate the formation of filopodial extensions, an early step in the formation of nascent spines, demonstrating that estrogen can alter the actin-dependent neuronal morphology. This linkage of estrogen communication to Cofilin via LIMK provides the functionality to the age-sensitive pLIMK-IR that we have observed in vivo.
Yuen
Genevieve S
GS
Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY 10065-6399, USA.
McEwen
Bruce S
BS
Akama
Keith T
KT
D051339:Actin Depolymerizing Factors / Q000378:metabolism*; D000375:Aging / Q000502:physiology; D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D051338:Cofilin 1 / Q000378:metabolism*; D004958:Estradiol / Q000494:pharmacology* / Q000502:physiology; D004967:Estrogens / Q000494:pharmacology / Q000502:physiology; D005260:Female; D054461:Lim Kinases / Q000502:physiology*; D051381:Rats
D051339:Actin Depolymerizing Factors; C495812:Cfl1 protein, rat; D051338:Cofilin 1; D004967:Estrogens; D004958:Estradiol; D054461:Lim Kinases