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Identification of a Thyroid Hormone Response Element in the Mouse Krüppel-Like Factor 9 Gene to Explain Its Postnatal Expression in the Brain

Department of Molecular, Cellular, and Developmental Biology, 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, The University of Michigan, Ann Arbor, Michigan 48109-1048. E-mail: rdenver{at}umich.edu.

Brain development is critically dependent on thyroid hormone (T₃). Krüppel-like factor 9 (Klf9) is a T₃-inducible gene in developing rat brain, and several lines of evidence support that KLF9 plays a key role in neuronal morphogenesis. Here we extend our findings to the mouse and demonstrate the presence of a functional T₃ response element (T₃RE) in the 5' flanking region of the mouse Klf9 gene. Klf9 mRNA is strongly induced in the mouse hippocampus and cerebellum in a developmental stage- and T₃-dependent manner. Computer analysis identified a near optimal direct repeat 4 (DR-4) T₃RE 3.8 kb upstream of the Klf9 transcription start site, and EMSAs showed that T₃ receptor (TR)-retinoid X receptor heterodimers bound to the T₃RE with high affinity. The T₃RE acts as a strong positive response element in transfection assays using a minimal heterologous promoter. In the mouse neuroblastoma cell line N2a[TRβ1], T₃ caused a dose-dependent up-regulation of Klf9 mRNA. Chromatin immunoprecipitation assays conducted with N2a[TRβ1] cells showed that TRs associated with the Klf9 T₃RE, and this association was promoted by T₃. Treatment of N2a[TRβ1] cells with T₃ led to hyperacetylation of histones 3 and 4 at the T₃RE site. Furthermore, TRs associated with the DR-4 T₃RE in postnatal d 4 mouse brain, and histone 4 acetylation was greater at this site compared with other regions of the Klf9 gene. Our study identifies a functional DR-4 T₃RE located in the mouse Klf9 gene to explain its regulation by T₃ during mammalian brain development.

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