Abstract
A conserved hormone response element, CNTFR-DR1 (5'-AGGTCAGAGGTCAGG-3'), has been identified in the 5th intron of the alpha component of the ciliary neurotrophic factor receptor (CNTFRalpha) gene for the human TR4 orphan receptor (TR4). Electrophoretic mobility shift assay showed a specific binding with high affinity (Kd = 0.066 nM) between TR4 and the CNTFR-DR1. A reporter gene assay using chloramphenicol acetyltransferase demonstrated that the 5th intron of CNTFRalpha has an enhancer activity which could be induced by TR4 in a dose-dependent manner. Furthermore, our in situ hybridization data showed that abundant TR4 transcripts were detected in adult brain, in regions of cortical and hippocampal neurons, as well as in many developing neural structures, including brain, spinal cord, ganglia (sympathetic and sensory), and neuronal epithelia (retinal, otic, olfactory, and gustatory). The striking similarities in the expression patterns of TR4 and CNTFRalpha in the developing and postnatal nervous systems further support the potential role of TR4 in neurogenesis. Collectively, these data suggest that the human CNTFRalpha gene could represent the first identified neural-specific gene induced by TR4.
Highlights
A conserved hormone response element, CNTFR-DR1 (5-AGGTCAGAGGTCAGG-3), has been identified in the 5th intron of the ␣ component of the ciliary neurotrophic factor receptor (CNTFR␣) gene for the human TR4 orphan receptor (TR4)
Cloning of the 5th Intron of the CNTFR␣ Gene—Based on the genomic organization and DNA sequence published by Valenzuela et al [20], the 5th intron of the human CNTFR␣ gene (CNTFR-I5) contains one perfect DR1 (5Ј-AGGTCACAGGTCA) and four copies of AGGTCA-like half-sites
Striking Similarities in the Expression Patterns of TR4 and CNTFR␣ within the Developing and Postnatal Nervous Systems—Widely overlapping expression domains of TR4 and CNTFR␣ [25] further strengthen our hypothesis that the regulation of CNTFR␣ by TR4 may happen in vivo
Summary
A conserved hormone response element, CNTFR-DR1 (5-AGGTCAGAGGTCAGG-3), has been identified in the 5th intron of the ␣ component of the ciliary neurotrophic factor receptor (CNTFR␣) gene for the human TR4 orphan receptor (TR4). The striking similarities in the expression patterns of TR4 and CNTFR␣ in the developing and postnatal nervous systems further support the potential role of TR4 in neurogenesis These data suggest that the human CNTFR␣ gene could represent the first identified neural-specific gene induced by TR4. Members of the steroid/thyroid hormone receptor superfamily are transcription factors that can bind to specific DNA sequences called hormone response elements (HRE) and thereby regulate the expression of their target genes [1]. This superfamily includes receptors for steroid, thyroid, vitamin D3, and retinoids, and a large number of orphan receptors whose cognate ligands are still unknown [1]. In vitro binding assays suggested that TR4 is capable of binding to 5Ј-AGGTCA direct repeats with 1– 6-base pair spacing (DR1-DR6). We hypothesized that the ␣ component of ciliary neurotrophic factor receptor (CNTFR␣) with DR1 in its 5th intron may be a target gene for TR4
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