Unliganded thyroid hormone receptor alpha1 impairs adult hippocampal neurogenesis.
Thyroid hormone regulates adult hippocampal neurogenesis, a process involved in key functions, such as learning, memory, and mood regulation. We addressed the role of thyroid hormone receptor TRα1 in adult hippocampal neurogenesis, using mice harboring a TRα1 null allele (TRα1(-/-)), overexpressing TRα1 6-fold (TRα2(-/-)), and a mutant TRα1 (TRα1(+/m)) with a 10-fold lower affinity to the ligand. While hippocampal progenitor proliferation was unaltered, TRα1(-/-) mice exhibited a significant increase in doublecortin-positive immature neurons and increased survival of bromodeoxyuridine-positive (BrdU(+)) progenitors as compared to wild-type controls. In contrast, the TRα1(+/m) and the TRα2(-/-) mice, where the overexpressed TRα1 acts as an aporeceptor, showed a significant decline in surviving BrdU(+) progenitors. TRα1(-/-) and TRα2(-/-) mice showed opposing effects on neurogenic markers like polysialylated neural cell adhesion molecule and stathmin. The decreased progenitor survival in the TRα2(-/-) and TRα1(+/m) mice could be rescued by thyroid hormone treatment, as was the decline in neuronal differentiation seen in the TRα1(+/m) mice. These mice also exhibited a decrease in NeuroD(+) cell numbers in the dentate gyrus, suggesting an effect on early postmitotic progenitors. Our results provide the first evidence of a role for unliganded TRα1 in modulating the deleterious effects of hypothyroidism on adult hippocampal neurogenesis.
Kapoor
Richa
R
Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, India.
van Hogerlinden
Max
M
Wallis
Karin
K
Ghosh
Himanish
H
Nordstrom
Kristina
K
Vennstrom
Bjorn
B
Vaidya
Vidita A
VA
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D005455:Fluorescent Antibody Technique; D006624:Hippocampus / Q000166:cytology* / Q000378:metabolism*; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D055495:Neurogenesis / Q000235:genetics / Q000502:physiology*; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D037021:Thyroid Hormone Receptors alpha / Q000235:genetics / Q000378:metabolism*
D037021:Thyroid Hormone Receptors alpha