title: Necdin controls Foxo1 acetylation in hypothalamic arcuate neurons to modulate the thyroid axis.
abstract: The forkhead transcription factor Foxo1 regulates energy homeostasis by modulating gene expression in the hypothalamus. Foxo1 undergoes post-translational modifications such as phosphorylation and acetylation, which modulate its functional activities. Sirtuin1 (Sirt1), a nicotinamide adenine dinucleotide-dependent protein deacetylase, regulates the acetylation status of Foxo1 in mammalian cells. Necdin, a pleiotropic protein required for neuronal development and survival, interacts with both Sirt1 and p53 to facilitate p53 deacetylation. The necdin gene (Ndn), an imprinted gene transcribed only from the paternal allele, is strongly expressed in hypothalamic neurons. Here, we demonstrate that necdin controls the acetylation status of Foxo1 in vivo in hypothalamic arcuate neurons to modulate the thyroid function. Necdin forms a stable ternary complex with Sirt1 and Foxo1, diminishes Foxo1 acetylation, and suppresses the transcriptional activity of Foxo1 in vitro. Paternal Ndn mutant mice express high levels of acetylated Foxo1 and mRNAs encoding agouti-related protein and neuropeptide Y in the hypothalamus in vivo during the juvenile period. The mutant mice exhibit endocrine dysfunction characteristic of hypothalamic hypothyroidism. Chemically induced hyperthyroidism and hypothyroidism lead to hypothalamic responses similar to those under necdin-deficient and excessive conditions, respectively, suggesting that thyroid hormone serves as a negative regulator of this system. These results suggest that necdin regulates Foxo1 acetylation and neuropeptide gene expression in the arcuate neurons to modulate the hypothalamic-pituitary-thyroid axis during development.
authors.affiliation: Laboratory of Regulation of Neuronal Development, Institute for Protein Research, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Hasegawa
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kawahara
authors.forename: Kazushiro
authors.initials: K
authors.lastname: Fujiwara
authors.forename: Mayumi
authors.initials: M
authors.lastname: Shimpuku
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Sasaki
authors.forename: Tadahiro
authors.initials: T
authors.lastname: Kitamura
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Yoshikawa
mesh_terms: D000107:Acetylation; D000367:Age Factors; D054369:Agouti-Related Protein / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D002245:Carbon Dioxide / Q000378:metabolism; D002461:Cell Line, Transformed; D047369:Chromatin Immunoprecipitation; D004797:Enzyme-Linked Immunosorbent Assay; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D007031:Hypothalamus / Q000166:cytology*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000378:metabolism*; D009474:Neurons / Q000502:physiology*; D009478:Neuropeptide Y / Q000378:metabolism; D009687:Nuclear Proteins / Q000172:deficiency / Q000378:metabolism*; D010101:Oxygen Consumption / Q000235:genetics; D012333:RNA, Messenger; D012097:Repressor Proteins / Q000378:metabolism*; D056564:Sirtuin 1 / Q000378:metabolism; D013961:Thyroid Gland / Q000378:metabolism*; D013972:Thyrotropin / Q000097:blood / Q000235:genetics; D013974:Thyroxine / Q000097:blood; D014162:Transfection; D014284:Triiodothyronine / Q000097:blood
chemical_list: D054369:Agouti-Related Protein; C515199:Agrp protein, mouse; D051858:Forkhead Transcription Factors; C432917:Foxp1 protein, mouse; D009419:Nerve Tissue Proteins; D009478:Neuropeptide Y; D009687:Nuclear Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins; C069766:necdin; D014284:Triiodothyronine; D002245:Carbon Dioxide; D013972:Thyrotropin; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D013974:Thyroxine