Thyroid Hormone Action in Cerebellum and Cerebral Cortex Development

Thyroid hormones (TH, including the prohormone thyroxine (T4) and its active deiodinated derivative 3,3′,5-triiodo-L-thyronine (T3)) are important regulators of vertebrates neurodevelopment. Specific transporters and deiodinases are required to ensure T3 access to the developing brain. T3 activates a number of differentiation processes in neuronal and glial cell types by binding to nuclear receptors, acting directly on transcription. Only few T3 target genes are currently known. Deeper investigations are urgently needed, considering that some chemicals present in food are believed to interfere with T3 signaling with putative neurotoxic consequences

LES CELLULES FOLLICULOSTELLAIRES : UNITES FONCTIONNELLES D'UNE VOIE DE COMMUNICATION A LONGUE DISTANCE DANS L'HYPOPHYSE ANTERIEURE.

The anterior pituitary is an endocrine interface between the brain and peripheral organs. This gland secretes hormones periodically, under the control of hypothalamic factors episodically released into the portal blood vessels of medium eminence. However, the hypothalamic influence does not fully explain the harmonisation of secretory activities of the distinct endocrine cell types scattered throughout the tissue. This indicates that a large-scale communication system exists within the anterior pituitary. We provide evidence for a new intrapituitary communication system by which information is rapidly transferred via the network of non-endocrine folliculostellate (FS) cells. In acute rat pituitary slices, preparation that keeps intact the tissue architecture, we discovered the hitherto unknown membrane excitability of FS cells. Excitability is one of the means to trigger long-range calcium waves in FS cells, which propagate to other FS cells by signaling through gap-junctions and can relay information between opposite regions of the gland. We also studied the in situ release by FS cells of interleukin-6, a cytokine known to stimulate the release of all pituitary hormones. PACAP stimulated IL-6 release from acute pituitary slices, most likely by acting at the IL-6 gene level. Strikingly, alteration of gap junction coupling alter the pattern of PACAP-induced IL-6 release. Because FS cells respond to central and peripheral stimuli and dialogue with endocrine cells, the form of large-scale intrapituitary communication described here may provide an efficient mechanism that orchestrates anterior pituitary functioning in response to physiological needs.L'hypophyse antérieure assure une interface endocrine entre le cerveau et les organes périphériques. En effet, cette glande sécrète de manière pulsatile ses différentes hormones dans la circulation générale sous l'influence de facteurs hypothalamiques déversés épisodiquement dans le système porte de l'éminence médiane. Toutefois, l'influence hypothalamique ne saurait à elle seule expliquer l'harmonisation des sécrétions des cellules d'un même type endocrine, qui sont distribuées de manière hétérogène au sein du parenchyme. Il existe sans doute des mécanismes permettant de coordonner l'activité des cellules endocrines à l'échelle de la glande entière. Au cours de cette thèse, nous avons montré la présence d'un mécanisme de communication intra-hypophysaire permettant un transfert rapide d'information au sein d'un réseau de cellules non-endocrines, les cellules folliculostellaires (FS). Ce travail réalisé sur des tranches épaisses d'hypophyse de rat, modèle qui maintient intacte l'architecture cordonale du tissu, a permis de mettre en évidence l'excitabilité membranaire des cellules FS, propriété jusqu'alors inconnue. Cette excitabilité sert de base à l'initiation de vagues calciques, qui peuvent se propager rapidement via des jonctions gap à des régions éloignées de la glande. Nous avons également étudié la libération d'interleukine-6 (IL-6) par les cellules FS. Cette cytokine est connue pour stimuler l'ensemble des sécrétions hormonales hypophysaires. La production d'IL-6 est stimulée par le PACAP. Ce neuropeptide semble agir directement au niveau du gène, et son effet dépend de l'état des communications intercellulaires au sein du réseau. Les cellules FS pouvant répondre à des stimuli d'origine centrale et périphérique, ainsi que dialoguer avec les cellules endocrines, l'ensemble de ces résultats montre que le réseau de cellules FS pourrait fournir un mécanisme efficace qui coordonnerait le fonctionnement de la glande en fonction des différents états physiologique

Les cellules folliculostellaires (unités fonctionnelles d'une voie de communication à longue distance dans l'hypophyse antérieure)

MONTPELLIER-BU Sciences (341722106) / SudocSudocFranceF

A Bimodal Influence of Thyroid Hormone on Cerebellum Oligodendrocyte Differentiation

International audienceThyroid hormone (T(3)) can trigger a massive differentiation of cultured oligodendrocytes precursor cells (OPC) by binding the nuclear T(3) receptor α1 (TRα1). Whether this reflects a physiological function of TRα1 remains uncertain. Using a recently generated mouse model, in which CRE/loxP recombination is used to block its function, we show that TRα1 acts at two levels for the in vivo differentiation of OPC in mouse cerebellum. At the early postnatal stage, it promotes the secretion of several neurotrophic factors by acting in Purkinje neurons and astrocytes, defining an environment suitable for OPC differentiation. At later stages, TRα1 acts in a cell-autonomous manner to ensure the complete arrest of OPC proliferation. These data explain contradictory observations made on various models and outline the importance of T(3) signaling both for synchronizing postnatal neurodevelopment and restraining OPC proliferation in adult brain

Minireview: Deciphering Direct and Indirect Influence of Thyroid Hormone With Mouse Genetics

International audienceT3, the active form of thyroid hormone, binds nuclear receptors that regulate the transcription of a large number of genes in many cell types. Unraveling the direct and indirect effect of this hormonal stimulation, and establishing links between these molecular events and the developmental and physiological functions of the hormone, is a major challenge. New mouse genetics tools, notably those based on Cre/loxP technology, are suitable to perform a multiscale analysis of T3 signaling and achieve this task

Hormone thyroïdienne et développement du cervelet : effets directs ou indirects ?

International audienceThyroid 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

The tiptop/teashirt genes regulate cell differentiation and renal physiology in Drosophila.

International audienceThe physiological activities of organs are underpinned by an interplay between the distinct cell types they contain. However, little is known about the genetic control of patterned cell differentiation during organ development. We show that the conserved Teashirt transcription factors are decisive for the differentiation of a subset of secretory cells, stellate cells, in Drosophila melanogaster renal tubules. Teashirt controls the expression of the water channel Drip, the chloride conductance channel CLC-a and the Leukokinin receptor (LKR), all of which characterise differentiated stellate cells and are required for primary urine production and responsiveness to diuretic stimuli. Teashirt also controls a dramatic transformation in cell morphology, from cuboidal to the eponymous stellate shape, during metamorphosis. teashirt interacts with cut, which encodes a transcription factor that underlies the differentiation of the primary, principal secretory cells, establishing a reciprocal negative-feedback loop that ensures the full differentiation of both cell types. Loss of teashirt leads to ineffective urine production, failure of homeostasis and premature lethality. Stellate cell-specific expression of the teashirt paralogue tiptop, which is not normally expressed in larval or adult stellate cells, almost completely rescues teashirt loss of expression from stellate cells. We demonstrate conservation in the expression of the family of tiptop/teashirt genes in lower insects and establish conservation in the targets of Teashirt transcription factors in mouse embryonic kidney

Lessons from monogenic causes of growth hormone deficiency

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