Thyroid hormone receptor beta mutation causes severe impairment of cerebellar development.
Cerebellar development on the postnatal period is mainly characterized by cellular proliferation in the external granular layer (EGL) followed by migration of granular cells in the molecular layer through the Bergmann glia (BG) fibers in order to form the granular layer in the adult. All these events are drastically affected by thyroid hormones (TH), which actions are mainly mediated by alpha (TRalpha) and beta (TRbeta) nuclear receptor isoforms. Here, we analyzed the effects of a natural human mutation (337T) in the TRbeta locus, which impairs T3 binding to its receptor, on the mouse cerebellum ontogenesis. We report that target inactivation of TRbeta-TH binding leads to a smaller cerebellum area characterized by impaired lamination and foliation. Further, TRbeta mutant mice presented severe deficits in proliferation of granular precursors, arborization of Purkinje cells and organization of BG fibers. Together, our data suggest that the action of TH via TRbeta regulates important events of cerebellar ontogenesis contributing to a better understanding of some neuroendocrine disorders. Further, our data correlate TRbeta with cerebellar foliation, and provide, for the first time, evidence of a receptor-mediated mechanism underlying TH actions on this event.
Portella
Aline Cristina
AC
Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, 21941-590, Rio de Janeiro, RJ, Brazil.
Carvalho
Fernando
F
Faustino
Larissa
L
Wondisford
Fredric E
FE
Ortiga-Carvalho
Tânia Maria
TM
Gomes
Flávia Carvalho Alcantara
FC
D000818:Animals; D000831:Animals, Newborn; D001369:Axons / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D002478:Cells, Cultured; D002531:Cerebellum / Q000002:abnormalities* / Q000378:metabolism* / Q000503:physiopathology; D003712:Dendrites / Q000378:metabolism / Q000473:pathology; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009421:Nervous System Malformations / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D055495:Neurogenesis / Q000235:genetics; D011485:Protein Binding / Q000235:genetics; D011689:Purkinje Cells / Q000378:metabolism / Q000473:pathology; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology; D013959:Thyroid Diseases / Q000150:complications; D037021:Thyroid Hormone Receptors alpha / Q000235:genetics; D037042:Thyroid Hormone Receptors beta / Q000235:genetics*; D013963:Thyroid Hormones / Q000378:metabolism*
D037021:Thyroid Hormone Receptors alpha; D037042:Thyroid Hormone Receptors beta; D013963:Thyroid Hormones