Deletion of the thyroid hormone receptor α1 prevents the structural alterations of the cerebellum induced by hypothyroidism

Beatriz Morte, Jimena Manzano, Thomas (Tom) Scanlan, Björn Vennström, Juan Bernal

Research output: Contribution to journalArticle

180 Citations (Scopus)

Abstract

Thyroid hormone (T3) controls critical aspects of cerebellar development, such as migration of postmitotic granule cells and terminal differentiation of Purkinje cells. T3 acts through nuclear receptors (TR) of two types, TRα1 and TRβ, that either repress or activate gene expression. We have analyzed the cerebellar structure of developing mice lacking the TRα1 isoform, which normally accounts for about 80% of T3 receptors in the cerebellum. Contrary to what was expected, granule cell migration and Purkinje cell differentiation were normal in the mutant mice. Even more striking was the fact that when neonatal hypothyroidism was induced, no alterations in cerebellar structure were observed in the mutant mice, whereas the wild-type mice showed delayed granule cell migration and arrested Purkinje cell growth. The results support the idea that repression by the TRα1 aporeceptor, and not the lack of thyroid hormone, is responsible for the hypothyroid phenotype. This conclusion was supported by experiments with the TRβ-selective compound GC-1. Treatment of hypothyroid animals with T3, which binds to TRα1 and TRβ, prevents any defect in cerebellar structure. In contrast, treatment with GC-1, which binds to TRβ but not TRα1, partially corrects Purkinje cell differentiation but has no effect on granule cell migration. Our data indicate that thyroid hormone has a permissive effect on cerebellar granule cell migration through derepression by the TRα1 isoform.

Original languageEnglish (US)
Pages (from-to)3985-3989
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume99
Issue number6
DOIs
StatePublished - Mar 19 2002
Externally publishedYes

Fingerprint

Thyroid Hormone Receptors
Cytoplasmic and Nuclear Receptors
Hypothyroidism
Cerebellum
Purkinje Cells
Cell Movement
Cell Differentiation
Thyroid Hormones
Protein Isoforms
Triiodothyronine
Phenotype
Gene Expression
Growth

Keywords

  • Cerebellar granule cells
  • Cretinism
  • Development
  • GC-1
  • Purkinje cells

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Deletion of the thyroid hormone receptor α1 prevents the structural alterations of the cerebellum induced by hypothyroidism. / Morte, Beatriz; Manzano, Jimena; Scanlan, Thomas (Tom); Vennström, Björn; Bernal, Juan.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 99, No. 6, 19.03.2002, p. 3985-3989.

Research output: Contribution to journalArticle

@article{a7c1e45baab04f349c56c6afe280817c,
title = "Deletion of the thyroid hormone receptor α1 prevents the structural alterations of the cerebellum induced by hypothyroidism",
abstract = "Thyroid hormone (T3) controls critical aspects of cerebellar development, such as migration of postmitotic granule cells and terminal differentiation of Purkinje cells. T3 acts through nuclear receptors (TR) of two types, TRα1 and TRβ, that either repress or activate gene expression. We have analyzed the cerebellar structure of developing mice lacking the TRα1 isoform, which normally accounts for about 80{\%} of T3 receptors in the cerebellum. Contrary to what was expected, granule cell migration and Purkinje cell differentiation were normal in the mutant mice. Even more striking was the fact that when neonatal hypothyroidism was induced, no alterations in cerebellar structure were observed in the mutant mice, whereas the wild-type mice showed delayed granule cell migration and arrested Purkinje cell growth. The results support the idea that repression by the TRα1 aporeceptor, and not the lack of thyroid hormone, is responsible for the hypothyroid phenotype. This conclusion was supported by experiments with the TRβ-selective compound GC-1. Treatment of hypothyroid animals with T3, which binds to TRα1 and TRβ, prevents any defect in cerebellar structure. In contrast, treatment with GC-1, which binds to TRβ but not TRα1, partially corrects Purkinje cell differentiation but has no effect on granule cell migration. Our data indicate that thyroid hormone has a permissive effect on cerebellar granule cell migration through derepression by the TRα1 isoform.",
keywords = "Cerebellar granule cells, Cretinism, Development, GC-1, Purkinje cells",
author = "Beatriz Morte and Jimena Manzano and Scanlan, {Thomas (Tom)} and Bj{\"o}rn Vennstr{\"o}m and Juan Bernal",
year = "2002",
month = "3",
day = "19",
doi = "10.1073/pnas.062413299",
language = "English (US)",
volume = "99",
pages = "3985--3989",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "6",

}

TY - JOUR

T1 - Deletion of the thyroid hormone receptor α1 prevents the structural alterations of the cerebellum induced by hypothyroidism

AU - Morte, Beatriz

AU - Manzano, Jimena

AU - Scanlan, Thomas (Tom)

AU - Vennström, Björn

AU - Bernal, Juan

PY - 2002/3/19

Y1 - 2002/3/19

N2 - Thyroid hormone (T3) controls critical aspects of cerebellar development, such as migration of postmitotic granule cells and terminal differentiation of Purkinje cells. T3 acts through nuclear receptors (TR) of two types, TRα1 and TRβ, that either repress or activate gene expression. We have analyzed the cerebellar structure of developing mice lacking the TRα1 isoform, which normally accounts for about 80% of T3 receptors in the cerebellum. Contrary to what was expected, granule cell migration and Purkinje cell differentiation were normal in the mutant mice. Even more striking was the fact that when neonatal hypothyroidism was induced, no alterations in cerebellar structure were observed in the mutant mice, whereas the wild-type mice showed delayed granule cell migration and arrested Purkinje cell growth. The results support the idea that repression by the TRα1 aporeceptor, and not the lack of thyroid hormone, is responsible for the hypothyroid phenotype. This conclusion was supported by experiments with the TRβ-selective compound GC-1. Treatment of hypothyroid animals with T3, which binds to TRα1 and TRβ, prevents any defect in cerebellar structure. In contrast, treatment with GC-1, which binds to TRβ but not TRα1, partially corrects Purkinje cell differentiation but has no effect on granule cell migration. Our data indicate that thyroid hormone has a permissive effect on cerebellar granule cell migration through derepression by the TRα1 isoform.

AB - Thyroid hormone (T3) controls critical aspects of cerebellar development, such as migration of postmitotic granule cells and terminal differentiation of Purkinje cells. T3 acts through nuclear receptors (TR) of two types, TRα1 and TRβ, that either repress or activate gene expression. We have analyzed the cerebellar structure of developing mice lacking the TRα1 isoform, which normally accounts for about 80% of T3 receptors in the cerebellum. Contrary to what was expected, granule cell migration and Purkinje cell differentiation were normal in the mutant mice. Even more striking was the fact that when neonatal hypothyroidism was induced, no alterations in cerebellar structure were observed in the mutant mice, whereas the wild-type mice showed delayed granule cell migration and arrested Purkinje cell growth. The results support the idea that repression by the TRα1 aporeceptor, and not the lack of thyroid hormone, is responsible for the hypothyroid phenotype. This conclusion was supported by experiments with the TRβ-selective compound GC-1. Treatment of hypothyroid animals with T3, which binds to TRα1 and TRβ, prevents any defect in cerebellar structure. In contrast, treatment with GC-1, which binds to TRβ but not TRα1, partially corrects Purkinje cell differentiation but has no effect on granule cell migration. Our data indicate that thyroid hormone has a permissive effect on cerebellar granule cell migration through derepression by the TRα1 isoform.

KW - Cerebellar granule cells

KW - Cretinism

KW - Development

KW - GC-1

KW - Purkinje cells

UR - http://www.scopus.com/inward/record.url?scp=0037133686&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0037133686&partnerID=8YFLogxK

U2 - 10.1073/pnas.062413299

DO - 10.1073/pnas.062413299

M3 - Article

C2 - 11891331

AN - SCOPUS:0037133686

VL - 99

SP - 3985

EP - 3989

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 6

ER -