Deletion of the thyroid hormone receptor alpha 1 prevents the structural alterations of the cerebellum induced by hypothyroidism.
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, TRalpha1 and TRbeta, that either repress or activate gene expression. We have analyzed the cerebellar structure of developing mice lacking the TRalpha1 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 TRalpha1 aporeceptor, and not the lack of thyroid hormone, is responsible for the hypothyroid phenotype. This conclusion was supported by experiments with the TRbeta-selective compound GC-1. Treatment of hypothyroid animals with T3, which binds to TRalpha1 and TRbeta, prevents any defect in cerebellar structure. In contrast, treatment with GC-1, which binds to TRbeta but not TRalpha1, 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 TRalpha1 isoform.
Morte
Beatriz
B
Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Cientificas-Universidad Autonoma de Madrid, Arturo Duperier 4, 28029 Madrid, Spain.
Manzano
Jimena
J
Scanlan
Thomas
T
Vennström
Björn
B
Bernal
Juan
J
D000818:Animals; D000831:Animals, Newborn; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D048429:Cell Size; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects / Q000254:growth & development / Q000473:pathology*; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics; D017353:Gene Deletion; D007037:Hypothyroidism / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D020033:Protein Isoforms / Q000172:deficiency / Q000235:genetics; D011689:Purkinje Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000172:deficiency* / Q000235:genetics; D011988:Receptors, Thyroid Hormone; D013963:Thyroid Hormones / Q000494:pharmacology; D014284:Triiodothyronine / Q000031:analogs & derivatives / Q000494:pharmacology
D004268:DNA-Binding Proteins; D020033:Protein Isoforms; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D011988:Receptors, Thyroid Hormone; D013963:Thyroid Hormones; D014284:Triiodothyronine