Hypothyroidism caused by a mutant thyroid hormone receptor alpha1 : consequences for development and physiology
Author: Sjögren, Maria
Date: 2008-02-01
Location: CMB auditorium, Berzelius väg 21
Time: 09.15
Department: Institutionen för cell- och molekylärbiologi (CMB) / Department of Cell and Molecular Biology
View/ Open:
Thesis (1.161Mb)
Abstract
Lack of sufficient thyroid hormone during pregnancy and early postnatal
development results in profound mental retardation and motor deficits
whereas altered thyroid status in the adult is associated with disturbed
metabolic homeostasis and impaired cardiac function. Thyroid hormone
mediates its effects through the distinct thyroid hormone receptors (TR)
TRalpha1 and TRbeta1-2, which are ligand-modulated transcription factors
that regulate gene expression both in the presence and absence of
hormone. Mutations in the TRbeta gene that decrease affinity to ligand
are associated with the well known syndrome Resistance to thyroid hormone
(RTH), which is characterized by elevated circulating levels of thyroid
hormone and a mixed hyper- and hypothyroid phenotype. However, no patient
with a corresponding mutation in the TRalpha gene has been found.
In this thesis, I describe the developmental and physiological consequences of a point mutation introduced into the mouse TRalpha1 gene. The mutation, originally identified in TRbeta (R438C) of RTH patients, reduces affinity for T3 10-fold, and causes the receptor to act as an aporeceptor unless challenged with high levels of thyroid hormone. We report that mice heterozygous for this mutation (TRalpha1+m mice) exhibit locomotor dysfunctions caused by insufficient supply of thyroid hormone during fetal/postnatal development. Furthermore, treatment with thyroid hormone during specific stages of development ameliorated these deficiencies. The locomotor dysfunctions correlated with delayed or perturbed development of several brain regions. Notably, we report that specific GABAergic cells in the neocortex were affected: the appearance of parvalbumin-immunoreactive GABAergic interneurons was severely delayed whereas the numbers of calretinin-immunoreactive cells were increased.
The TRalpha1+m mice also exhibited increased metabolic rate, hyperphagia and resistance to obesity despite their reduced body temperature. This is likely due to increased hypothalamic output to brown adipose tissue: adaptation to thermoneutrality normalized most metabolic parameters. Further analysis of hypothalamic function in the TRalpha1+m mice supports this view. Finally, we demonstrate that the mutant TRalpha1 severely affects calcium handling in mouse cardiomyocytes, which in larger organisms may result in heart disease.
In conclusion, we have identified novel and important properties of the TRalpha1 aporeceptor in neuronal development as well as in physiological processes such as thermogenesis and cardiac function. That the mutant mice have normal serum levels of thyroid hormone offers an explanation for why corresponding patients have not been found. However, our data provide information potentially critical for identification of patients and for their treatment.
In this thesis, I describe the developmental and physiological consequences of a point mutation introduced into the mouse TRalpha1 gene. The mutation, originally identified in TRbeta (R438C) of RTH patients, reduces affinity for T3 10-fold, and causes the receptor to act as an aporeceptor unless challenged with high levels of thyroid hormone. We report that mice heterozygous for this mutation (TRalpha1+m mice) exhibit locomotor dysfunctions caused by insufficient supply of thyroid hormone during fetal/postnatal development. Furthermore, treatment with thyroid hormone during specific stages of development ameliorated these deficiencies. The locomotor dysfunctions correlated with delayed or perturbed development of several brain regions. Notably, we report that specific GABAergic cells in the neocortex were affected: the appearance of parvalbumin-immunoreactive GABAergic interneurons was severely delayed whereas the numbers of calretinin-immunoreactive cells were increased.
The TRalpha1+m mice also exhibited increased metabolic rate, hyperphagia and resistance to obesity despite their reduced body temperature. This is likely due to increased hypothalamic output to brown adipose tissue: adaptation to thermoneutrality normalized most metabolic parameters. Further analysis of hypothalamic function in the TRalpha1+m mice supports this view. Finally, we demonstrate that the mutant TRalpha1 severely affects calcium handling in mouse cardiomyocytes, which in larger organisms may result in heart disease.
In conclusion, we have identified novel and important properties of the TRalpha1 aporeceptor in neuronal development as well as in physiological processes such as thermogenesis and cardiac function. That the mutant mice have normal serum levels of thyroid hormone offers an explanation for why corresponding patients have not been found. However, our data provide information potentially critical for identification of patients and for their treatment.
List of papers:
I. Wallis K, Sjögren M, van Hogerlinden M, Silberberg G, Fisahn A, Nordström K, Larsson L, Westerblad H, Morreale de Escobar G, Shupliakov O, Vennström B (2008). Locomotor deficiencies and aberrant development of subtype-specific GABAergic interneurons caused by an unliganded thyroid hormone receptor alpha1. [Accepted]
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Sjögren M, Alkemade A, Mittag J, Nordström K, Katz A, Rozell B, Westerblad H, Arner A, Vennström B (2007). Hypermetabolism in mice caused by the central action of an unliganded thyroid hormone receptor alpha1. EMBO J. 26(21): 4535-45. Epub 2007 Oct 11.
Fulltext (DOI)
Pubmed
View record in Web of Science®
III. Alkemade A, Sjögren M, Nordström K, Vennström B (2007). Unliganded thyroid hormone receptor alpha1 disrupts the neuroendocrine response to fasting. [Manuscript]
IV. Tavi P, Sjögren M, Lunde PK, Zhang SJ, Abbate F, Vennström B, Westerblad H (2005). Impaired Ca2+ handling and contraction in cardiomyocytes from mice with a dominant negative thyroid hormone receptor alpha1. J Mol Cell Cardiol. 38(4): 655-63.
Fulltext (DOI)
Pubmed
View record in Web of Science®
I. Wallis K, Sjögren M, van Hogerlinden M, Silberberg G, Fisahn A, Nordström K, Larsson L, Westerblad H, Morreale de Escobar G, Shupliakov O, Vennström B (2008). Locomotor deficiencies and aberrant development of subtype-specific GABAergic interneurons caused by an unliganded thyroid hormone receptor alpha1. [Accepted]
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Sjögren M, Alkemade A, Mittag J, Nordström K, Katz A, Rozell B, Westerblad H, Arner A, Vennström B (2007). Hypermetabolism in mice caused by the central action of an unliganded thyroid hormone receptor alpha1. EMBO J. 26(21): 4535-45. Epub 2007 Oct 11.
Fulltext (DOI)
Pubmed
View record in Web of Science®
III. Alkemade A, Sjögren M, Nordström K, Vennström B (2007). Unliganded thyroid hormone receptor alpha1 disrupts the neuroendocrine response to fasting. [Manuscript]
IV. Tavi P, Sjögren M, Lunde PK, Zhang SJ, Abbate F, Vennström B, Westerblad H (2005). Impaired Ca2+ handling and contraction in cardiomyocytes from mice with a dominant negative thyroid hormone receptor alpha1. J Mol Cell Cardiol. 38(4): 655-63.
Fulltext (DOI)
Pubmed
View record in Web of Science®
Issue date: 2008-01-11
Rights:
Publication year: 2008
ISBN: 978-91-7357-384-9
Statistics
Total Visits
Views | |
---|---|
Hypothyroidism ...(legacy) | 799 |
Hypothyroidism ... | 179 |
Total Visits Per Month
October 2023 | November 2023 | December 2023 | January 2024 | February 2024 | March 2024 | April 2024 | |
---|---|---|---|---|---|---|---|
Hypothyroidism ... | 2 | 3 | 1 | 1 | 0 | 0 | 0 |
File Visits
Views | |
---|---|
thesis.pdf(legacy) | 544 |
thesis.pdf | 273 |
thesis.pdf.txt(legacy) | 2 |
Top country views
Views | |
---|---|
United States | 422 |
Sweden | 71 |
China | 63 |
Germany | 59 |
Finland | 15 |
South Korea | 14 |
United Kingdom | 11 |
Russia | 10 |
India | 8 |
Ukraine | 7 |
Top cities views
Views | |
---|---|
Ashburn | 38 |
Sunnyvale | 34 |
Beijing | 31 |
Romeo | 30 |
Kiez | 18 |
Lansing | 17 |
Seoul | 14 |
Stockholm | 12 |
Nürnberg | 11 |
Atlanta | 10 |