Peroxisome Proliferator-Activated Receptor β/δ in the Brain: Facts and Hypothesis

peroxisome proliferator-activated receptors (PPARs) are nuclear receptors acting as lipid sensors. Besides its metabolic activity in peripheral organs, the PPAR beta/delta isotype is highly expressed in the brain and its deletion in mice induces a brain developmental defect. Nevertheless, exploration of PPARβ action in the central nervous system remains sketchy. The lipid content alteration observed in PPARβ null brains and the positive action of PPARβ agonists on oligodendrocyte differentiation, a process characterized by lipid accumulation, suggest that PPARβ acts on the fatty acids and/or cholesterol metabolisms in the brain. PPARβ could also regulate central inflammation and antioxidant mechanisms in the damaged brain. Even if not fully understood, the neuroprotective effect of PPARβ agonists highlights their potential benefit to treat various acute or chronic neurological disorders. In this perspective, we need to better understand the basic function of PPARβ in the brain. This review proposes different leads for future researches

A point mutation in the AF-2 domain of thyroid hormone receptor alpha1 expressed after CRE mediated recombination partially recapitulates hypothyroidism.

Thyroid hormones act directly on transcription by binding to TRα1, TRβ1, TRβ2 nuclear receptors, regulating many aspects of post-natal development and homeostasis. To precisely analyze the implication of the widely expressed TRα1 isoform in this pleiotropic action, we have generated transgenic mice with a point mutation in the TRα1 coding sequence, which is expressed only after CRE/loxP mediated DNA recombination. The amino-acid change prevents interaction between TRα1 and histone acetyltransferase coactivators and the release of corepressors. Early expression of this dominant-negative receptor deeply affects post-natal development and adult homeostasis, recapitulating many aspects of congenital and adult hypothyroidism, except in tissues and cells where TRβ1 and TRβ2 are predominantly expressed. Both respective abundance and intrinsic properties of TRα1 and TRβ1/2 seems to govern specificity of action

EFFETS PHYSIOLOGIQUES ET PATHOGENIQUES DE L'APORECEPTEUR DE L'HORMONE THYROÏDIENNE ALPHA 1 AU COURS DU DEVELOPPEMENT DE LA SOURIS

Date de rédaction : Février / Mars 2007Thyroid hormone (T3) has pleiotropic functions during development. Congenital hypothyroidism results in severe mental retardation. Using transgenic reporter mice, we showed that T3 action is highly heterogeneous in pre and post-natal brain. The regulation of gene expression by T3 involves binding of the hormone to TR nuclear receptors acting as T3-dependant transcription factors. We identified new T3 direct target genes in postnatal cerebellum, but the T3 signaling cascade is still unknown, because of complexe cell cell interactions. To suppress T3 response in a specific cell type and at a specific time, we created new transgenic mice expressing a mutated TR?1 in a conditional manner. Constitutive mutants have a hypothyroid like phenotype. This confirms the importance of unliganded TR?1 receptor in hypothyroidism pathogenesis. The conditional system will permit to dissect in vivo T3 action.L'hormone thyroïdienne (T3) a des fonctions pléiotropiques au cours du développement. Un déficit congénital de T3 est responsable d'un retard mental sévère. Grâce à des souris possédant un transgène rapporteur, nous avons montré que l'activité de l'hormone est très hétérogène dans le cerveau pré et post-natal. T3 agit via les récepteurs nucléaires TR pour réguler la transcription de gènes-cibles. De nouveaux gènes-cibles ont été identifiés dans le cervelet post-natal, mais la cascade de signalisation demeure inconnue, en raison d'interactions cellulaires complexes. Pour supprimer la réponse à T3 à un moment donné, dans une cellule donnée, des souris exprimant de façon conditionnelle un récepteur TR?1 muté ont été générées. Les mutants constitutifs ont un phénotype très proche de l'hypothyroïdie, ce qui confirme l'implication majeure du récepteur TR?1 non lié à T3 dans la pathogénie de l'hypothyroïdie. Le système conditionnel permettra de disséquer le mécanisme d'action de T3 in vivo

Effets physiologiques et pathogéniques de l aporécepteur de l hormone thyroïdienne alpha 1 au cours du développement de la souris

L hormone thyroïdienne (T3) a des fonctions pléiotropiques au cours du développement. Un déficit congénital de T3 est responsable d un retard mental sévère. Grâce à des souris possédant un transgène rapporteur, nous avons montré que l activité de l hormone est très hétérogène dans le cerveau pré et post-natal. T3 agit via les récepteurs nucléaires TR pour réguler la transcription de gènes-cibles. De nouveaux gènes-cibles ont été identifiés dans le cervelet post-natal, mais la cascade de signalisation demeure inconnue, en raison d interactions cellulaires complexes. Pour supprimer la réponse à T3 à un moment donné, dans une cellule donnée, des souris exprimant de façon conditionnelle un récepteur TR 1 muté ont été générées. Les mutants constitutifs ont un phénotype très proche de l hypothyroïdie, ce qui confirme l implication majeure du récepteur TR 1 non lié à T3 dans la pathogénie de l hypothyroïdie. Le système conditionnel permettra de disséquer le mécanisme d action de T3 in vivo.Thyroid hormone (T3) has pleiotropic functions during development. Congenital hypothyroidism results in severe mental retardation. Using transgenic reporter mice, we showed that T3 action is highly heterogeneous in pre and post-natal brain. The regulation of gene expression by T3 involves binding of the hormone to TR nuclear receptors acting as T3-dependant transcription factors. We identified new T3 direct target genes in postnatal cerebellum, but the T3 signaling cascade is still unknown, because of complexe cell cell interactions. To suppress T3 response in a specific cell type and at a specific time, we created new transgenic mice expressing a mutated TR?1 in a conditional manner. Constitutive mutants have a hypothyroid like phenotype. This confirms the importance of unliganded TR?1 receptor in hypothyroidism pathogenesis. The conditional system will permit to dissect in vivo T3 action.LYON-ENS Sciences (693872304) / SudocSudocFranceF

L'hormone thyroïdienne et ses récepteurs : la génétique de la souris clarifie-t-elle la situation ?

Chez les vertébrés, la forme active de l'hormone thyroïdienne (T3) agit directement sur la transcription en modifiant la conformation des récepteurs nucléaires TR (TRα1, TRβ1 et TRβ2) encodés par les gènes THRA et THRB. Ces récepteurs sont fixés sur l'ADN au niveau d'éléments de réponse spécifiques indépendamment de la présence d'hormone. La génétique de la souris a clarifié la fonction respective de chaque isoforme, déterminée en grande partie par le mode d'expression des gènes THRA et THRB. Elle a aussi révélé l'importance de l'action négative des TR en absence de ligand non seulement dans les conditions pathologiques que physiologique

Thyroid hormone receptor alpha is a molecular switch of cardiac function between fetal and postnatal life

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Thyroid hormone signaling is highly heterogeneous during pre- and postnatal brain development

International audienc

Type 3 Deiodinase Deficiency Causes Spatial and Temporal Alterations in Brain T3 Signaling that Are Dissociated from Serum Thyroid Hormone Levels

The type 3 deiodinase (D3) is an enzyme that inactivates thyroid hormones (TH) and is highly expressed during development and in the central nervous system. D3-deficient (D3KO) mice develop markedly elevated serum T3 level in the perinatal period. In adulthood, circulating T4 and T3 levels are reduced due to functional deficits in the thyroid axis and peripheral tissues (i.e. liver) show evidence of decreased TH action. Given the importance of TH for brain development, we aimed to assess TH action in the brain of D3KO mice at different developmental stages and determine to what extent it correlates with serum TH parameters. We used a transgenic mouse model (FINDT3) that expresses the reporter gene β-galactosidase (β-gal) in the central nervous system as a readout of local TH availability. Together with experiments determining expression levels of TH-regulated genes, our results show that after a state of thyrotoxicosis in early development, most regions of the D3KO brain show evidence of decreased TH action at weaning age. However, later in adulthood and in old age, the brain again manifests a thyrotoxic state, despite reduced serum TH levels. These region-specific changes in brain TH status during the life span of the animal provide novel insight into the important role of the D3 in the developing and adult brain. Our results suggest that, even if serum concentrations of TH are normal or low, impaired D3 activity may result in excessive TH action in multiple brain regions, with potential consequences of altered neural function that may be of clinical relevance to neurological and neuroendocrine disorders

A combined approach identifies a limited number of new thyroid hormone target genes in post-natal mouse cerebellum.

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