TY - JOUR
T1 - Thyroid hormone receptor Β mutation causes severe impairment of cerebellar development
AU - Portella, Aline Cristina
AU - Carvalho, Fernando
AU - Faustino, Larissa
AU - Wondisford, Fredric E.
AU - Ortiga-Carvalho, Tânia Maria
AU - Gomes, Flávia Carvalho Alcantara
N1 - Funding Information:
We thank Ismael Gomes and Marcelo Meloni for technical assistance and the Program for Technological Development in Tools for Health-PDTIS-FIOCRUZ for the use of its facilities. This study was supported by grants from the Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ) , Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) , Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) , and Sociedade Brasileira de Endocrinologia e Metabologia (SBEM) .
PY - 2010/5
Y1 - 2010/5
N2 - 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 (TRα) and beta (TRΒ) nuclear receptor isoforms. Here, we analyzed the effects of a natural human mutation (337T) in the TRΒlocus, which impairs T3 binding to its receptor, on the mouse cerebellum ontogenesis. We report that target inactivation of TRΒ-TH binding leads to a smaller cerebellum area characterized by impaired lamination and foliation. Further, TRΒ 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 TRβ regulates important events of cerebellar ontogenesis contributing to a better understanding of some neuroendocrine disorders. Further, our data correlate TRΒ with cerebellar foliation, and provide, for the first time, evidence of a receptor-mediated mechanism underlying TH actions on this event.
AB - 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 (TRα) and beta (TRΒ) nuclear receptor isoforms. Here, we analyzed the effects of a natural human mutation (337T) in the TRΒlocus, which impairs T3 binding to its receptor, on the mouse cerebellum ontogenesis. We report that target inactivation of TRΒ-TH binding leads to a smaller cerebellum area characterized by impaired lamination and foliation. Further, TRΒ 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 TRβ regulates important events of cerebellar ontogenesis contributing to a better understanding of some neuroendocrine disorders. Further, our data correlate TRΒ with cerebellar foliation, and provide, for the first time, evidence of a receptor-mediated mechanism underlying TH actions on this event.
KW - Bergmann glia
KW - Cerebellum
KW - Foliation
KW - Nuclear receptors
KW - TRΒ
KW - Thyroid hormone
UR - http://www.scopus.com/inward/record.url?scp=77950341607&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77950341607&partnerID=8YFLogxK
U2 - 10.1016/j.mcn.2010.02.004
DO - 10.1016/j.mcn.2010.02.004
M3 - Article
C2 - 20193766
AN - SCOPUS:77950341607
SN - 1044-7431
VL - 44
SP - 68
EP - 77
JO - Molecular and Cellular Neuroscience
JF - Molecular and Cellular Neuroscience
IS - 1
ER -