Hypothyroidism alters the expression of Bcl-2 family genes to induce enhanced apoptosis in the developing cerebellum

Singh, Rajesh; Upadhyay, Geeta; Kumar, Sanjeev; Kapoor, Amit; Kumar, Ashok; Tiwari, Meenakshi; Godbole, Madan M.

doi:10.1677/joe.0.1760039

Cited by 63 publications

(56 citation statements)

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“…At the molecular level, we observed reduced expression of the proapoptotic gene Bad and increased expression of the antiapoptotic gene Bcl2 in vitro. This was in accordance with reduced Bcl2 expression in other CNS cell types due to hypothyroidism, such as cerebellar neurons (Muller et al, 1995;Singh et al, 2003), and shows the importance of thyroid hormone for cell survival in the brain.…”

Section: Discussionsupporting

confidence: 82%

Stimulatory Effects of Thyroid Hormone on Brain Angiogenesis in vivo and in vitro

Zhang

Cooper-Kuhn

Nannmark

et al. 2009

J Cereb Blood Flow Metab

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Thyroid hormone is critical for the proper development of the central nervous system. However, the specific role of thyroid hormone on brain angiogenesis remains poorly understood. Treatment of rats from birth to postnatal day 21 (P21) with propylthiouracil (PTU), a reversible blocker of triiodothyronine (T3) synthesis, resulted in decreased brain angiogenesis, as indicated by reduced complexity and density of microvessels. However, when PTU was withdrawn at P22, these parameters were fully recovered by P90. These changes were paralleled by an altered expression of vascular endothelial growth factor A (Vegfa) and basic fibroblast growth factor (Fgf2). Physiologic concentrations of T3 and thyroxine (T4) stimulated proliferation and tubulogenesis of rat brainderived endothelial (RBE4) cells in vitro. Protein and mRNA levels of VEGF-A and FGF-2 increased after T3 stimulation of RBE4 cells. The thyroid hormone receptor blocker NH-3 abolished T3-induced Fgf2 and Vegfa upregulation, indicating a receptor-mediated effect. Thyroid hormone inhibited the apoptosis in RBE4 cells and altered mRNA levels of apoptosis-related genes, namely Bcl2 and Bad. The present results show that thyroid hormone has a substantial impact on vasculature development in the brain. Pathologically altered vascularization could, therefore, be a contributing factor to the neurologic deficits induced by thyroid hormone deficiency.

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Section: Discussionsupporting

confidence: 82%

Stimulatory Effects of Thyroid Hormone on Brain Angiogenesis in vivo and in vitro

Zhang

Cooper-Kuhn

Nannmark

et al. 2009

J Cereb Blood Flow Metab

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“…Here, we report that TH deficiency leads to structural alterations in mitochondria and enhanced translocation of apoptogenic proteins to cytosol, which results in the enhanced apoptosis during cerebellar neurogenesis observed previously (Xiao & Nikodem 1998, Singh et al 2003.…”

Section: Introductionmentioning

confidence: 68%

“…In euthyroid conditions, we found that Bax was predominantly localized in mitochondria during early developmental stages and decreased with age. Previously, we observed the high expression of Bcl-2 and Bcl-x L under euthyroid conditions (Singh et al 2003). It is reasonable to assume that Figure 5 Analysis of AIF translocation to cytosol.…”

Section: Discussionmentioning

confidence: 88%

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Hypothyroidism alters mitochondrial morphology and induces release of apoptogenic proteins during rat cerebellar development

Singh

Upadhyay²,

Godbole

2003

Journal of Endocrinology

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Thyroid hormone (TH) deficiency leads to extensive apoptosis during cerebellar development, but the mechanism still remains unclear. Different signals also converge on mitochondria during apoptosis to induce the release of apoptogenic proteins that activate proteolytic cascade through specific enzymes called caspases. Here we studied the effect of hypothyroidism on alterations in mitochondrial structure and translocation of apoptogenic molecules during rat cerebellar development. Structural analysis of mitochondria was studied by electron microscopy. The translocation of apoptogenic molecules was analyzed by Western blotting. TH deficiency led to vacuolization, enlargement and decrease in the number of cristae. The majority of the proapoptotic molecule, Bax, was localized in mitochondria under hypothyroid conditions whereas a limited presence of Bax was detected in the euthyroid state. Translocation of cytochrome c, apoptosis-inducing factor (AIF) and second mitochondrial-derived activator of caspases (SMAC) from mitochondria to cytosol was detected primarily in early developmental stages in the hypothyroid condition. These experimental results demonstrate that TH maintains mitochondrial architecture and inhibits the release of apoptogenic molecules to prevent excess apoptosis during cerebellar development.

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“…This was documented initially in children with congenital hypothyroidism (Leneman et al, 2001;Hindmarsh, 2002;Hrytsiuk et al, 2002;Salerno et al, 2002;Rovet and Daneman, 2003). These findings were followed by animal studies mainly focused on cerebellar development, which occurs largely postnatally (Koibuchi and Chin, 2000;Thompson and Potter, 2000;Morte et al, 2002;Singh et al, 2003). Moreover, observations in humans (Cao et al, 1994;Haddow et al, 1999;Pop et al, 1999;Pop et al, 2003) provided important evidence that THs are also essential in early (fetal) brain development, and that the associated neurological deficits depend on the timing and severity of TH insufficiency.…”

Section: Nervous Systemmentioning

confidence: 97%

Thyroid hormones and the control of cell proliferation or cell differentiation: Paradox or duality?

Kress

Samarut

Plateroti

2009

Molecular and Cellular Endocrinology

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Thyroid hormones and the control of cell proliferation or cell differentiation: paradox or duality?. Molecular and Cellular Endocrinology, Elsevier, 2009, 313 (1-2) This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. SummaryAmphibian metamorphosis perfectly illustrates a key paradox: thyroid hormones control diverse cellular processes depending on the tissue context. This point is also reinforced by a recent accumulation of evidence. For example, thyroid hormones and their nuclear receptor TRs have been described to function in different systems in synergy and/or in antagonism with other signaling pathways. This interaction helps explain their pleiotropic roles. This review summarizes the most important advances in this field, focusing in particular on the key action of thyroid hormones in controlling the balance between the processes of cell proliferation and cell differentiation in a few organs, with special attention paid to the intestine. We highlight similarities between the cellular and molecular events occurring during postnatal intestinal maturation at metamorphosis in amphibians, and comparable events observed at weaning in mice. 1-Introduction1.1 Thyroid hormone production Thyroid hormones (THs), L-thyroxine or T4 and 3,5,3'-L-triiodothyronine or T3, are essential for the development of several organs, including the central nervous system, skeleton, heart, intestine, skeletal muscle and sensory organs. Moreover, they also have important regulatory effects on oxygen consumption and metabolic rate (Oppenheimer et al., 1987). The follicular cells of the thyroid gland synthesize and secrete both hormones, but T4 is the most abundant. This process is under the control of circulating THs levels through the hypothalamuspituitary-thyroid feedback regulatory loop (rev. in Fredric and Wondisford, 2004). The intracellular concentration of T3 is dependent upon the uptake of T3 and T4, and their subsequent metabolism (Bianco and Kim, 2006). In fact, both hormones are actively transported across the cell membrane by specific transporter proteins, of which monocarboxylate transporter-8 is the best characterized (Dumitrescu et al., 2004;Friesema et al., 2004; rev. in Refetoff andDumitrescu, 2007 andVisser et al., 2007). Three iodothyronine deiodinase selenoenzymes (D1, D2 and D3) regulate TH activation and catabolism (Bianco and Kim, 2006). D1 and D2 catalyze the 5'-deiodination of T4 to its active metabolite T3. T3 is generated from the activity of D1, which is the main source of circulating T3. In contrast, D2 is the isoenzyme primarily responsible for local production of T3 in target cells. T3 derived from ...

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Hypothyroidism alters the expression of Bcl-2 family genes to induce enhanced apoptosis in the developing cerebellum

Cited by 63 publications

References 39 publications

Stimulatory Effects of Thyroid Hormone on Brain Angiogenesis in vivo and in vitro

Stimulatory Effects of Thyroid Hormone on Brain Angiogenesis in vivo and in vitro

Hypothyroidism alters mitochondrial morphology and induces release of apoptogenic proteins during rat cerebellar development

Thyroid hormones and the control of cell proliferation or cell differentiation: Paradox or duality?

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