Transcriptional Repression of Neurotrophin Receptor trkBby Thyroid Hormone in the Developing Rat Brain

Abstract

Expression of the neurotrophin receptor trkB is regulated by thyroid hormone (T3) during development of the rat brain. trkB mRNA levels, coding for the fulllength and the truncated isoforms, are increased in the cerebral cortex of neonatal experimental hypothyroid animals. Run-on transcription assays with nuclei from postnatal day 15, hypothyroid, and control cerebral cortices demonstrated that an increase in the transcription rate of the trkB gene accounts for the observed effect. Transient transfection experiments using a reporter plasmid containing a 7-kilobase pair DNA fragment upstream of the mouse trkB gene showed that unliganded thyroid hormone receptor (T3R) increases promoter activity, whereas addition of T3 reverses that activity below basal levels. Deletion analysis shows that the T3-dependent repression requires binding of the T3R to a specific region located downstream of the transcription start site. This region, at nucleotide position ؊465/؊432, contains an array of thyroid hormone response halfsites that bind preferentially T3R as heterodimers with retinoid X receptor and whose deletion causes loss of the T3-dependent repression. These half-sites are able to confer negative regulation by T3 to a heterologous promoter, thus indicating the functionality of these sequences. These results demonstrate that, in the developing rat brain, T3 down-regulates the expression of the trkB gene through the active repression of a novel negative response element located downstream of its transcription initiation site.

Ca2+, CREB and krüppel: A novel KLF7-binding element conserved in mouse and human TRKB promoters is required for CREB-dependent transcription

“…An alternative explanation is that resting Ca 2+ levels in unstimulated neurons may be sufficient to partially activate TRKB expression. In either case, the requirement for TCaRE3 for basal TRKB transcription may explain triiodo-thyronine (T3)-dependent inhibition of TRKB reported in rat neuroblastoma cells (Pombo et al, 2000). TCaRE3 encompasses one of four potential T3 half sites (TGTCCT) required for T3-dependent inhibition TRKB; activation of T3 receptors may inhibit TRKB expression by displacing KLF7.…”

Cumulative Activation of Akt and Consequent Inhibition of Glycogen Synthase Kinase-3 by Brain-Derived Neurotrophic Factor and Insulin-Like Growth Factor-1 in Cultured Hippocampal Neurons

“…Our neurons were cultured under somewhat different conditions, possibly resulting in differences in the level of expression of TrkB receptors relative to IGF-1 receptors. Unlike the B27 supplement used in their studies, our cultures did not contain thyroid hormone (T3), which has been reported to transcriptionally repress TrkB synthesis (Pombo et al, 2000). In addition, the concentration of insulin in our medium was decreased before neuronal studies to avoid baseline occupancy of IGF-1 receptors.…”

A Novel Mechanism of Thyroid Hormone-dependent Negative Regulation by Thyroid Hormone Receptor, Nuclear Receptor Corepressor (NCoR), and GAGA-binding Factor on the Rat CD44 Promoter

“…Other studies suggest that TR binds directly to TREs or TRElike sequences for negative regulation by T 3 (9,10) and that various types of nTRE sequences resembling TREs are located in the promoters (trkB and amyloid precursor protein) (11)(12)(13), the first exons (c-myc) (14), and the 3Ј-untranslated regions (rat growth hormone and Clone 144) (15). For example, the TSH␣ promoter contains palindromic TREs necessary for negative regulation by T 3 (16), whereas mouse TSH␤ has a DRϩ2 TRE that includes a TRE near the TSS (9,17,18).…”