title: Action of thyroxine on the survival and neurite maintenance of cerebellar granule neurons in culture.
abstract: Developmental hypothyroidism causes severe impairments in the cerebellum. To understand the role of thyroid hormones (THs) in cerebellar development, we examined the effect of three different THs, thyroxine (T4), 3,5,3'-triidothyronine (T3), and 3,3',5'-triiodothyronine (reverse T3; rT3), on the survival and morphology of cerebellar granule neurons (CGNs) in culture and found novel actions specific to T4. Rat CGNs obtained at postnatal day 6 were first cultured for 2 days in serum-containing medium with 25 mM K(+) (K25), then switched to serum-free medium with physiological 5 mM K(+) (K5) or with K25 and cultured for an additional 2 or 4 days. CGNs underwent apoptosis in K5 but survived in K25. Addition of T4 at concentrations of 100-200 nM but not T3 or rT3 rescued CGNs from cell death in K5 in a dose-dependent manner. Furthermore, 200 nM T4 was also effective in maintaining the neurites of CGNs in K5. In K5, T4 suppressed tau phosphorylation at two developmentally regulated sites as well as phosphorylation of c-jun N-terminal kinase (JNK) necessary for its activation and localization to axons. These results suggest that, during cerebellar development, T4 exerts its activity in cell survival and neurite maintenance in a manner distinct from the other two thyroid hormones through regulating the activity and localization of JNK.
authors.affiliation: Department of Chemistry and Biological Science, School of Science and Engineering, Aoyama Gakuin University, Kanagawa, Japan.
authors.forename: Koshi
authors.initials: K
authors.lastname: Oyanagi
authors.forename: Takayuki
authors.initials: T
authors.lastname: Negishi
authors.forename: Tomoko
authors.initials: T
authors.lastname: Tashiro
mesh_terms: D000199:Actins / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology*; D004305:Dose-Response Relationship, Drug; D020287:In Situ Nick-End Labeling; D066298:In Vitro Techniques; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D016501:Neurites / Q000187:drug effects*; D009474:Neurons / Q000166:cytology* / Q000187:drug effects; D009924:Organ Culture Techniques; D011188:Potassium / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D013974:Thyroxine / Q000494:pharmacology*; D014404:Tubulin / Q000378:metabolism
chemical_list: D000199:Actins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D014404:Tubulin; D048670:MAP Kinase Kinase 4; D013974:Thyroxine; D011188:Potassium
keywords: cell survival; cerebellar granule cells; phosphorylation; tau proteins; thyroid hormones