No abstract

In humans, inactivating mutations in the gene of the thyroid hormone transporter monocarboxylate transporter 8 (MCT8; SLC16A2) lead to severe forms of psychomotor retardation combined with imbalanced thyroid hormone serum levels. The MCT8-null mice described here, however, developed without overt deficits but also exhibited distorted 3,5,3′-triiodothyronine (T3) and thyroxine (T4) serum levels, resulting in increased hepatic activity of type 1 deiodinase (D1). In the mutants' brains, entry of T4 was not affected, but uptake of T3 was diminished. Moreover, the T4 and T3 content in the brain of MCT8-null mice was decreased, the activity of D2 was increased, and D3 activity was decreased, indicating the hypothyroid state of this tissue. In the CNS, analysis of T3 target genes revealed that in the mutants, the neuronal T3 uptake was impaired in an area-specific manner, with strongly elevated thyrotropin-releasing hormone transcript levels in the hypothalamic paraventricular nucleus and slightly decreased RC3 mRNA expression in striatal neurons; however, cerebellar Purkinje cells appeared unaffected, since they did not exhibit dendritic outgrowth defects and responded normally to T3 treatment in vitro. In conclusion, the circulating thyroid hormone levels of MCT8-null mice closely resemble those of humans with MCT8 mutations, yet in the mice, CNS development is only partially affected.

C lassically, the anterior pituitary is considered as a secondary oscillator obeying mainly hypothalamic factors, either increasing or decreasing secretion of pituitary hormones, which are released in an episodic manner at the base of the median eminence (1-4). The portal blood vessels form the interorgan communication system driving the hypothalamic inputs to the anterior pituitary. They collect the transmitters released by hypothalamic nerve endings at the primary capillary plexus level and slowly distribute them in the endocrine parenchyma via the arborescence of pituitary sinusoids between the columnar units of pituitary cells (''cell cords'') (5, 6). Over the last three decades, many studies carried out in isolated endocrine cells have provided strong evidence that endocrine cells generate action potential-driven rises in cytosolic Ca 2ϩ concentration ([Ca 2ϩ ] i ) that are probably the keystones of dynamic adjustment of numerous cellular functions, including exocytosis and gene expression (7-9). Recently, the technique of acute slice preparations applied to the anterior pituitary revealed that endocrine cells do fire short-term [Ca 2ϩ ] i transients because of their electrical activity in situ (10, 11).However, the activity of the gland as a whole does not reflect the average of independent dynamics of cellular messages that occur in the distinct endocrine cell types scattered throughout the tissue. In this respect, one puzzling finding is the persistence of pulsatile releasing profiles of hormones when the gland is disconnected from the hypothalamic inputs (12, 13). This indicates that a large-scale communication system exists within the anterior pituitary. Despite the wealth of information on cell-tocell mechanisms between endocrine cells that comprise the release of paracrine factors (14) and gap junction signaling (10), spreading of spatial information that crosses the limits of single cell cords could not be explained by these mechanisms.Because a highly efficient process spreading spatial information to the entire gland and even to pituitary subregions has not been reported yet, we explored here whether nonendocrine folliculostellate (FS) cells can support long-distance information transfer within the gland. FS cells display a star-shaped cytoplasmic configuration intermingled between hormone-secreting cells. The organization of FS cells within the parenchyma forms a three-dimensional anatomical network, in the meshes of which the endocrine cells reside (15, 16). Very little is known about the functioning of this FS cell network, in particular with regard to the dynamics of cellular͞intercellular messages. To study the behavior of this network, we measured multicellular changes in [Ca 2ϩ ] i , a messenger involved in a wide range of cell-to-cell communication mechanisms (17-23), electrophysiological properties of FS cells, and intercellular diffusion of dyes in acute pituitary slices. We show here that the FS cell network forms a functional intrapituitary circuitry in which information-Ca 2ϩ signa...

Recent genetic analysis in several patients presenting a severe form of X-linked psychomotor retardation combined with abnormal thyroid hormone (TH) levels have revealed mutations or deletions in the gene of the monocarboxylate transporter 8 (MCT8). Because in vitro MCT8 functions as a TH transporter, the complex clinical picture of these patients indicated an important role for MCT8 in TH-dependent processes of brain development. To provide a clue to the cellular function of MCT8 in brain, we studied the expression of MCT8 mRNA in the murine central nervous system by in situ hybridization histochemistry. In addition to the choroid plexus structures, the highest transcript levels were found in neo- and allocortical regions (e.g. olfactory bulb, cerebral cortex, hippocampus, and amygdala), moderate signal intensities in striatum and cerebellum, and low levels in a few neuroendocrine nuclei. Colocalization studies revealed that MCT8 is predominantly expressed in neurons. Together with the spatiotemporal expression pattern of MCT8 during the perinatal period, these results strongly indicate that MCT8 plays an important role for proper central nervous system development by transporting TH into neurons as its main target cells.