Thyroid hormone controls a number of developmental and physiological processes in the brain by directly acting on gene expression. Transcriptome analyses in rodent identified a number of thyroid ...hormone regulated genes in several brain areas at different stages. Genome wide analysis of chromatin occupancy in a neural cell line also identified a subset of genes which transcription is likely to be directly regulated by thyroid hormone receptors in neurons. However, the abundance of these data and apparent discrepancies between studies brought some confusion.
We present here a meta-analysis of available data to identify recurrent themes in thyroid hormone action in brain cells. This provides a curated list of 734 regulated genes in rodent brain, and highlights a small number of likely direct target genes. Some of these genes are also regulated in amphibians during metamorphosis. This article is part of a Special Issue entitled: Nuclear receptors in animal development.
•Thousands of thyroid hormone regulated genes have been reported in brain cells.•We present of a curated list of 734 genes reported more than once.•Comparison with other neural and non-neural systems identifies a shared subset.•Comparison with amphibians identifies few conserved regulations.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Thyroid hormones act directly on gene transcription in the post-natal developing cerebellum, controlling neuronal, and glial cell differentiation. We have combined three experimental approaches to ...identify the target genes that are underlying this phenomenon: 1) a microarray analysis of gene expression to identify hormone responsive genes in the cerebellum of Pax8−/− mice, a transgenic mouse model of congenital hypothyroidism; 2) a similar microarray analysis on primary culture of cerebellum neurons; and 3) a bioinformatics screen of conserved putative-binding sites in the mouse genome. This identifies surprisingly a small set of target genes, which, for some of them, might be key regulators of cerebellum development and neuronal differentiation.
The genes encoding thyroid hormone receptor α and β (
TRα and
TRβ) encode four thyroid hormone receptors and four variant isoforms with antagonistic properties. Because of this complexity, numerous ...models of
TR mutation have been developed to understand the functions of specific receptors. In total, 13 mutant strains are now available. Phenotype analysis has shown that the two genes serve distinct functions:
TRα is crucial for postnatal development and cardiac function, whereas
TRβ mainly controls inner ear and retina development, liver metabolism and thyroid hormone levels. These mouse mutant strains also provide us with the unique opportunity to address the respective contribution of each receptor isoform and isotype
in vivo and highlight the
in vivo importance of the ligand-independent function of the
TR gene products.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The second International Society of Paediatric Oncology (SIOP) study for rhabdomyosarcoma (MMT84) had several goals. The two principal aims were: (1) to improve the survival of children with ...rhabdomyosarcoma; and (2) to reduce the late effects from therapy by restricting the indications for surgery and/or radiotherapy after good response to initial chemotherapy. A further aim was to investigate the role of high-dose chemotherapy in young patients with parameningeal primary tumours. 186 previously untreated eligible patients entered the study. Patients with completely resected primary tumour received three courses of IVA (ifosfamide, vincristine and actinomycin D). Patients with incompletely resected tumour received six to 10 courses of IVA according to stage. Patients achieving complete remission with chemotherapy alone did not usually receive radiotherapy or undergo extensive surgery, but patients remaining in partial remission received local therapy with surgery and/or radiotherapy. Only patients over 5 years of age with parameningeal disease and patients over 12 years with tumours at any site were given systematic irradiation. Complete remission was achieved in 91% (170/186) of all patients. With a median follow-up of 8 years, the 5-year overall survival was 68% (±3% standard error of the mean (SEM)) and the 5-year event-free survival 53% (±4% SEM). These results show an improvement over previous SIOP study (RMS75) in which survival was 52% and event-free survival was 47%. Among the 54 patients who exhibited isolated local relapse, 35% (19/54) survived in further remission longer than 2 years after retreatment, including local therapy (surgery±radiotherapy). Analysis of the overall burden of therapy received by all surviving children (including primary treatment and treatment for relapse if required) showed that 24% (28/116) were treated by limited surgery followed by three courses of IVA, 29% (34/116) were treated by chemotherapy alone (after initial biopsy) and 13% (15/116) received chemotherapy plus conservative local treatment (limited surgery or radiotherapy for residual disease). Only 34% (39/116) received intensive local therapy defined as radical wide field radiotherapy or radical surgery or both. Compared with the results obtained in the previous SIOP study, treatment in MMT84 was based on response to initial chemotherapy and, despite an overall reduction of the use of local therapy, significantly improved survival for patients with non-metastatic disease. This trial, also for the first time, provides evidence that retreatment after local relapse can achieve long-term second remissions.
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IJS, IMTLJ, KILJ, KISLJ, NUK, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
We have generated transgenic reporter mice to analyze the spatio-temporal distribution of thyroid hormone signaling during mouse brain development. The reporter system, utilizing a chimeric yeast ...Gal4 DNA-binding domain–thyroid hormone α ligand-binding domain fusion protein to drive lacZ expression, revealed that thyroid hormone signaling starts in the midbrain roof several days before the onset of thyroid gland function, and that it remains highly heterogeneous in the central nervous system throughout pre- and postnatal development. We speculate that this heterogeneity might provide neural cells with positional information during development.
Thyroid hormone (T₃) exerts an important influence on neurodevelopment, which can be analysed by using the postnatal development of rodent cerebellum as a model. T₃ acts on all types of neuronal and ...glial cells, which express at least the TRα1 nuclear receptor, and, for some of them, the TRβ1 isoform. However, as T₃ also activates the secretion of neurotrophins, it can also affect cellular differentiation in an indirect manner. Ongoing experiments, based on mouse genetics and genome wide analysis of gene expression, provide a promising way to study the basic mechanisms of neurodevelopment. This review describes new mouse genetics models and recent advance in this field.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Thyroid hormone is a major regulator of postnatal brain development, but the precise molecular mechanisms underlying its action in this organ remain poorly understood. We used microarray analysis to ...identify new target genes in brain. Thyroid hormone treatment of hypothyroid
Pax8
−/−
knockout mice, which lack thyroid follicular cells, had a very limited global effect on brain transcripts. This analysis mainly identified
cyclin D2 as a new thyroid hormone target gene in the cerebellum of hypothyroid mice. Thyroid hormone receptor (
TRα and/or
TRβ) knockout mice studies provided further genetic evidence that
cyclin D2 is likely to mediate the antiapoptotic effect exerted by thyroid hormone on the cerebellum external granular layer neuroblasts but that this transcriptional activation is not directly exerted by the thyroid hormone receptors.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract Thyroid hormone (T3) exerts an important influence on neurodevelopment, which can be analysed by using the postnatal development of rodent cerebellum as a model. T3 acts on all types of ...neuronal and glial cells, which express at least the TRα1 nuclear receptor, and, for some of them, the TRβ1 isoform. However, as T3 also activates the secretion of neurotrophins, it can also affect cellular differentiation in an indirect manner. Ongoing experiments, based on mouse genetics and genome wide analysis of gene expression, provide a promising way to study the basic mechanisms of neurodevelopment. This review describes new mouse genetics models and recent advance in this field.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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