[Show abstract][Hide abstract] ABSTRACT: Thyroid hormones (THs) are vital for normal postnatal development. Extracellular TH distributor proteins create an intravascular reservoir of THs. Transthyretin (TTR) is a TH distributor protein in the circulatory system and is the only TH distributor protein synthesised in the central nervous system. We investigated the phenotype of TTR null mice during development. Total and free T(4) (3',5',3,5-tetraiodo-L-thyronine) and free T(3) (3',3,5-triiodo-L-thyronine) in plasma were significantly reduced in 14 day old (P14) TTR null mice. TTR null mice also displayed a delayed suckling-to-weaning transition, decreased muscle mass, delayed growth and retarded longitudinal bone growth. In addition, ileums from postnatal day 0 (P0) TTR null mice displayed disordered architecture and contained fewer goblet cells than wild type. Protein concentrations in cerebrospinal fluid from P0 and P14 TTR null mice were higher than in age-matched wild type mice. In contrast to the current literature based on analyses of adult TTR null mice, our results demonstrate that TTR has an important and non-redundant role in influencing the development of several organs.
Full-text · Article · Oct 2012 · AJP Endocrinology and Metabolism
[Show abstract][Hide abstract] ABSTRACT: Transthyretin (TTR) is an extracellular thyroid hormone (TH) distributor protein. The TH distributor proteins ensure the adequate distribution of THs throughout the body, buffer against excess TH uptake into cells and maintain an extrathyroidal reserve of THs that may protect against TH deficiency when TH demand is increased. Thyroid hormones are vital for normal postnatal development. Thus, the postnatal development and growth of tissues responsive to THs has been investigated in TTR null mice. Although the developmental surge in plasma T4 concentrations was evident in 2-week-old TTR null mice, total and free T4 in the plasma were significantly reduced. Characteristics of the developing TTR null mice included delayed suckling-to-weaning transition, delayed onset of growth and retarded longitudinal bone growth. In addition, ileums from newborn TTR null mice displayed disordered cellular structure and contained fewer goblet cells. Although TH homeostasis within the brain of the developing TTR null mice did not appear to be compromised, subtle differences suggested a degree of immaturity in the developing brain, such as higher protein concentrations of cerebrospinal fluid from newborn and 2-week-old TTR null mice than in age-matched wild type mice. Collectively, these studies demonstrate the importance of TTR during post-natal development and suggest that the development of the central nervous system is essentially preserved at the expense of peripheral tissues in TTR null mice.
[Show abstract][Hide abstract] ABSTRACT: Thyroid hormones are essential for vertebrate development. There is a characteristic rise in thyroid hormone levels in blood during critical periods of thyroid hormone-regulated development. Thyroid hormones are lipophilic compounds, which readily partition from an aqueous environment into a lipid environment. Thyroid hormone distributor proteins are required to ensure adequate distribution of thyroid hormones, throughout the aqueous environment of the blood, and to counteract the avid partitioning of thyroid hormones into the lipid environment of cell membranes. In human blood, these proteins are albumin, transthyretin and thyroxine-binding globulin. We analyzed the developmental profile of thyroid hormone distributor proteins in serum from a representative of each order of marsupials (M. eugenii; S.crassicaudata), a reptile (C. porosus), in two species of salmonoid fishes (S. salar; O. tshawytsch), and throughout a calendar year for sea bream (S. aurata). We demonstrated that during development, these animals have a thyroid hormone distributor protein present in their blood which is not present in the adult blood. At least in mammals, this additional protein has higher affinity for thyroid hormones than the thyroid hormone distributor proteins in the blood of the adult. In fish, reptile and polyprotodont marsupial, this protein was transthyretin. In a diprotodont marsupial, it was thyroxine-binding globulin. We propose an hypothesis that an augmented thyroid hormone distributor protein network contributes to the rise in total thyroid hormone levels in the blood during development.
Full-text · Article · Jun 2005 · AJP Regulatory Integrative and Comparative Physiology
[Show abstract][Hide abstract] ABSTRACT: Glucocorticoid (GC) hormones cause pronounced T cell apoptosis, particularly in immature thymic T cells. This is possibly due to tissue-specific regulation of the glucocorticoid receptor (GR) gene. In mice the GR gene is transcribed from five separate promoters designated: 1A, 1B, 1C, 1D, and 1E. Nearly all cells express GR from promoters 1B-1E, but the activity of the 1A promoter has only been reported in the whole thymus or lymphocyte cell lines. To directly assess the role of GR promoter use in sensitivity to glucocorticoid-induced cell death, we have compared the activity of the GR 1A promoter with GC sensitivity in different mouse lymphocyte populations. We report that GR 1A promoter activity is restricted to thymocyte and peripheral lymphocyte populations and the cortex of the brain. The relative level of expression of the 1A promoter to the 1B-1E promoters within a lymphocyte population was found to directly correlate with susceptibility to GC-induced cell death, with the extremely GC-sensitive CD4+CD8+ thymocytes having the highest levels of GR 1A promoter activity, and the relatively GC-resistant alphabetaTCR+CD24(int/low) thymocytes and peripheral T cells having the lowest levels. DNA sequencing of the mouse GR 1A promoter revealed a putative glucocorticoid-response element. Furthermore, GR 1A promoter use and GR protein levels were increased by GC treatment in thymocytes, but not in splenocytes. These data suggest that tissue-specific differences in GR promoter use determine T cell sensitivity to glucocorticoid-induced cell death.
Full-text · Article · Oct 2004 · The Journal of Immunology
[Show abstract][Hide abstract] ABSTRACT: Glucocorticoids provide important signals for maturation of the fetal lung and antenatal glucocorticoids are used to reduce the respiratory insufficiency suffered by preterm infants. To further understand the role of glucocorticoids in fetal lung maturation, we have analyzed mice with a targeted null mutation for the glucocorticoid receptor (GR) gene, which severely retards lung development. The lungs of fetal GR-null mice have increased lung weight and DNA content, are condensed and hypercellular, with reduced septal thinning leading to a 6-fold increase in the airway to capillary diffusion distance. In fetal GR-null mice, mRNA levels of the type II epithelial cell surfactant protein genes A and C were reduced by approximately 50%. Analysis of epithelial cell types by electron microscopy revealed that the proportions of type II cells were increased by approximately 30%, whereas the proportions of type-I cells were markedly reduced (by approximately 50%). Similarly, we found a 50% reduction in mRNA levels for T1alpha and aquaporin-5, two type I cell-specific markers, and a 20% reduction in aquaporin-1 mRNA levels. This demonstrates that during murine embryonic development, receptor-mediated glucocorticoid signaling facilitates the differentiation of epithelial cells into type I cells, but is not obligatory for type II cell differentiation.
Full-text · Article · May 2004 · American Journal of Respiratory Cell and Molecular Biology