An unliganded thyroid hormone receptor causes severe neurological dysfunction

Koshi Hashimoto; Flavio H Curty; Patricia P Borges; Charlotte E Lee; E. Dale Abel; Joel K Elmquist; Ronald N Cohen; Fredric E Wondisford

doi:10.1073/pnas.051454698

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An unliganded thyroid hormone receptor causes severe neurological dysfunction

Journal article

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Peer reviewed

An unliganded thyroid hormone receptor causes severe neurological dysfunction

Koshi Hashimoto, Flavio H Curty, Patricia P Borges, Charlotte E Lee, E. Dale Abel, Joel K Elmquist, Ronald N Cohen and Fredric E Wondisford

Proceedings of the National Academy of Sciences - PNAS, Vol.98(7), pp.3998-4003

03/27/2001

DOI: 10.1073/pnas.051454698

PMCID: PMC31168

PMID: 11274423

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Abstract

Congenital hypothyroidism and the thyroid hormone (T 3 ) resistance syndrome are associated with severe central nervous system (CNS) dysfunction. Because thyroid hormones are thought to act principally by binding to their nuclear receptors (TRs), it is unexplained why TR knock-out animals are reported to have normal CNS structure and function. To investigate this discrepancy further, a T 3 binding mutation was introduced into the mouse TR-β locus by homologous recombination. Because of this T 3 binding defect, the mutant TR constitutively interacts with corepressor proteins and mimics the hypothyroid state, regardless of the circulating thyroid hormone concentrations. Severe abnormalities in cerebellar development and function and abnormal hippocampal gene expression and learning were found. These findings demonstrate the specific and deleterious action of unliganded TR in the brain and suggest the importance of corepressors bound to TR in the pathogenesis of hypothyroidism.

Biological Sciences

Details

Title: Subtitle: An unliganded thyroid hormone receptor causes severe neurological dysfunction
Creators: Koshi Hashimoto - Section of Endocrinology and Metabolism, Department of Medicine, University of Chicago, Chicago, IL 60637; and
Flavio H Curty - Section of Endocrinology and Metabolism, Department of Medicine, University of Chicago, Chicago, IL 60637; and
Patricia P Borges - Section of Endocrinology and Metabolism, Department of Medicine, University of Chicago, Chicago, IL 60637; and
Charlotte E Lee - Section of Endocrinology and Metabolism, Department of Medicine, University of Chicago, Chicago, IL 60637; and
E. Dale Abel - Section of Endocrinology and Metabolism, Department of Medicine, University of Chicago, Chicago, IL 60637; and
Joel K Elmquist - Section of Endocrinology and Metabolism, Department of Medicine, University of Chicago, Chicago, IL 60637; and
Ronald N Cohen - Section of Endocrinology and Metabolism, Department of Medicine, University of Chicago, Chicago, IL 60637; and
Fredric E Wondisford - Section of Endocrinology and Metabolism, Department of Medicine, University of Chicago, Chicago, IL 60637; and
Resource Type: Journal article
Publication Details: Proceedings of the National Academy of Sciences - PNAS, Vol.98(7), pp.3998-4003
DOI: 10.1073/pnas.051454698
PMID: 11274423
PMCID: PMC31168
NLM abbreviation: Proc Natl Acad Sci U S A
ISSN: 0027-8424
eISSN: 1091-6490
Publisher: National Academy of Sciences
Language: English
Date published: 03/27/2001
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Endocrinology and Metabolism; Internal Medicine
Record Identifier: 9984024542002771

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