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Stressor and Glucocorticoid-Dependent Induction of the Immediate Early Gene Krüppel-Like Factor 9: Implications for Neural Development and Plasticity

Departments of Molecular, Cellular and Developmental Biology (R.M.B., F.H., P.B., R.J.D.) and Ecology and Evolutionary Biology (R.J.D.), The University of Michigan, Ann Arbor, Michigan 48109-1048

Address all correspondence and requests for reprints to: Dr. Robert J. Denver, Department of Molecular, Cellular, and Developmental Biology, 3065C Kraus Natural Science Building, 830 North University Avenue, The University of Michigan, Ann Arbor, Michigan 48109-1048. E-mail: rdenver{at}umich.edu.

Krüppel-like factor 9 (KLF9) is a thyroid hormone-induced, immediate early gene implicated in neural development in vertebrates. We analyzed stressor and glucocorticoid (GC)-dependent regulation of KLF9 expression in the brain of the frog Xenopus laevis, and investigated a possible role for KLF9 in neuronal differentiation. Exposure to shaking/confinement stressor increased plasma corticosterone (CORT) concentration, and KLF9 immunoreactivity in several brain regions, which included the medial amygdala and bed nucleus of the stria terminalis, anterior preoptic area (homologous to the mammalian paraventricular nucleus), and optic tectum (homologous to the mammalian superior colliculus). The stressor-induced KLF9 mRNA expression in the brain was blocked by pretreatment with the GC receptor antagonist RU486, or mimicked by injection of CORT. Treatment with CORT also caused a rapid and dose-dependent increase in KLF9 mRNA in X. laevis XTC-2 cells that was resistant to inhibition of protein synthesis. The action of CORT on KLF9 expression in XTC-2 cells was blocked by RU486, but not by the mineralocorticoid receptor antagonist spironolactone. To test for functional consequences of up-regulation of KLF9, we introduced a KLF9 expression plasmid into living tadpole brain by electroporation-mediated gene transfer. Forced expression of KLF9 in tadpole brain caused an increase in Golgi-stained cells, reflective of neuronal differentiation/maturation. Our results support that KLF9 is a direct, GC receptor target gene that is induced by stress, and functions as an intermediary in the actions of GCs on brain gene expression and neuronal structure.

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				R. J. Denver and K. E. Williamson Identification of a Thyroid Hormone Response Element in the Mouse Kruppel-Like Factor 9 Gene to Explain Its Postnatal Expression in the Brain Endocrinology, August 1, 2009; 150(8): 3935 - 3943. [Abstract] [Full Text] [PDF]