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The Journal of Neuroscience, November 19, 2003, 23(33):10604-10612

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Development/Plasticity/Repair
Thyroid Hormone Induces Cerebellar Purkinje Cell Dendritic Development via the Thyroid Hormone Receptor 1

Heike Heuer and Carol Ann Mason

Department of Pathology, Center for Neurobiology and Behavior, Columbia University, College of Physicians and Surgeons, New York, New York 10032

The thyroid hormone L-3,3',5-triiodothyronine (T3) plays an important role during cerebellar development. Perinatal T3 deficiency leads to severe cellular perturbations, among them a striking reduction in the growth and branching of Purkinje cell dendritic arborization. The molecular mechanisms underlying these effects are poorly understood. Despite the well documented broad expression of thyroid hormone receptors (TRs), analysis of different TR-deficient mice has failed to provide detailed information about the function of distinct TRs during neuronal development. The cerebellar cell culture systems offer an excellent model by which to study the effects of T3, because differentiation of cerebellar neurons in mixed and purified cultures proceeds in the absence of serum that contains T3. Addition of T3 to cerebellar cultures causes a dramatic increase in Purkinje cell dendrite branching and caliber in a dose- and time-dependent manner. Furthermore, we demonstrate for the first time that T3 acts on Purkinje cells directly through TR1 expressed on the Purkinje cell and not on the granule cell, the presynaptic partner of Purkinje cells. In contrast, TR isoforms are not involved, because Purkinje cells derived from TR^-/- mice show the same T3 responsiveness as wild-type cells. T3-promoted Purkinje cell differentiation was not mediated via neurotrophins, as suggested previously, because dendritogenesis of Purkinje cells from BDNF^-/- mice could be effectively stimulated in vitro by T3 treatment. Furthermore, the effects of T3 observed were not abolished by tyrosine kinase receptor B (TrkB)-IgG, TrkC-IgG, or K252a, agents known to block the actions of neurotrophin. These results indicate that T3 directly affects Purkinje cell differentiation through activation of the TR1.

Key words: thyroid hormone; T3; TR; Purkinje cell; neurotrophins; BDNF; NT3; K252a; dendrite development; cerebellum

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Received April 29, 2003; revised August 25, 2003; accepted September 24, 2003.

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