title: Developmental hypothyroidism abolishes bilateral differences in sonic hedgehog gene control in the rat hippocampal dentate gyrus.
abstract: Both developmental and adult-stage hypothyroidism disrupt rat hippocampal neurogenesis. We previously showed that exposing mouse offspring to manganese permanently disrupts hippocampal neurogenesis and abolishes the asymmetric distribution of cells expressing Mid1, a molecule regulated by sonic hedgehog (Shh) signaling. The present study examined the involvement of Shh signaling on the disruption of hippocampal neurogenesis in rats with hypothyroidism. Pregnant rats were treated with methimazole (MMI) at 0 or 200 ppm in the drinking water from gestation day 10-21 days after delivery (developmental hypothyroidism). Adult male rats were treated with MMI in the same manner from postnatal day (PND) 46 to PND 77 (adult-stage hypothyroidism). Developmental hypothyroidism reduced the number of Mid1(+) cells within the subgranular zone of the dentate gyrus of offspring on PND 21, and consequently abolished the normal asymmetric predominance of Mid1(+) cells on the right side through the adult stage. In control animals, Shh was expressed in a subpopulation of hilar neurons, showing asymmetric distribution with left side predominance on PND 21; however, this asymmetry did not continue through the adult stage. Developmental hypothyroidism increased Shh(+) neurons bilaterally and abolished the asymmetric distribution pattern on PND 21. Adult hypothyroidism also disrupted the asymmetric distribution of Mid1(+) cells but did not affect the distribution of Shh(+) hilar neurons. The results suggest that the hippocampal neurogenesis disruption seen in hypothyroidism involves changes in asymmetric Shh(+) neuron distribution in developmental hypothyroidism and altered Mid1 expression in both developmental and adult-stage hypothyroidism.
authors.affiliation: *Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, Saiwai-cho, Fuchu-shi, Tokyo 183-8509; and Pathogenetic Veterinary Science, United Graduate School of Veterinary Sciences, Gifu University, 1-1 Yanagido, Gifu-shi, Gifu 501-1193, Japan *Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, Saiwai-cho, Fuchu-shi, Tokyo 183-8509; and Pathogenetic Veterinary Science, United Graduate School of Veterinary Sciences, Gifu University, 1-1 Yanagido, Gifu-shi, Gifu 501-1193, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Tanaka
authors.affiliation: *Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, Saiwai-cho, Fuchu-shi, Tokyo 183-8509; and Pathogenetic Veterinary Science, United Graduate School of Veterinary Sciences, Gifu University, 1-1 Yanagido, Gifu-shi, Gifu 501-1193, Japan.
authors.forename: Liyun
authors.initials: L
authors.lastname: Wang
authors.affiliation: *Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, Saiwai-cho, Fuchu-shi, Tokyo 183-8509; and Pathogenetic Veterinary Science, United Graduate School of Veterinary Sciences, Gifu University, 1-1 Yanagido, Gifu-shi, Gifu 501-1193, Japan *Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, Saiwai-cho, Fuchu-shi, Tokyo 183-8509; and Pathogenetic Veterinary Science, United Graduate School of Veterinary Sciences, Gifu University, 1-1 Yanagido, Gifu-shi, Gifu 501-1193, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Kimura
authors.affiliation: *Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, Saiwai-cho, Fuchu-shi, Tokyo 183-8509; and Pathogenetic Veterinary Science, United Graduate School of Veterinary Sciences, Gifu University, 1-1 Yanagido, Gifu-shi, Gifu 501-1193, Japan *Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, Saiwai-cho, Fuchu-shi, Tokyo 183-8509; and Pathogenetic Veterinary Science, United Graduate School of Veterinary Sciences, Gifu University, 1-1 Yanagido, Gifu-shi, Gifu 501-1193, Japan.
authors.forename: Hajime
authors.initials: H
authors.lastname: Abe
authors.affiliation: *Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, Saiwai-cho, Fuchu-shi, Tokyo 183-8509; and Pathogenetic Veterinary Science, United Graduate School of Veterinary Sciences, Gifu University, 1-1 Yanagido, Gifu-shi, Gifu 501-1193, Japan *Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, Saiwai-cho, Fuchu-shi, Tokyo 183-8509; and Pathogenetic Veterinary Science, United Graduate School of Veterinary Sciences, Gifu University, 1-1 Yanagido, Gifu-shi, Gifu 501-1193, Japan.
authors.forename: Sayaka
authors.initials: S
authors.lastname: Mizukami
authors.affiliation: *Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, Saiwai-cho, Fuchu-shi, Tokyo 183-8509; and Pathogenetic Veterinary Science, United Graduate School of Veterinary Sciences, Gifu University, 1-1 Yanagido, Gifu-shi, Gifu 501-1193, Japan.
authors.forename: Toshinori
authors.initials: T
authors.lastname: Yoshida
authors.affiliation: *Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, Saiwai-cho, Fuchu-shi, Tokyo 183-8509; and Pathogenetic Veterinary Science, United Graduate School of Veterinary Sciences, Gifu University, 1-1 Yanagido, Gifu-shi, Gifu 501-1193, Japan mshibuta@cc.tuat.ac.jp.
authors.forename: Makoto
authors.initials: M
authors.lastname: Shibutani
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D018891:Dentate Gyrus / Q000378:metabolism* / Q000503:physiopathology; D004195:Disease Models, Animal; D005260:Female; D018507:Gene Expression Regulation, Developmental; D005865:Gestational Age; D053823:Hedgehog Proteins / Q000378:metabolism*; D007037:Hypothyroidism / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D007150:Immunohistochemistry; D008297:Male; D008713:Methimazole; D055495:Neurogenesis; D009474:Neurons / Q000378:metabolism; D011247:Pregnancy; D012333:RNA, Messenger / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014158:Transcription, Genetic
chemical_list: D053823:Hedgehog Proteins; D012333:RNA, Messenger; C546888:Shh protein, rat; D008713:Methimazole
keywords: hippocampus; hypothyroidism; midline 1 (Mid1); neurogenesis; rat; sonic hedgehog (Shh)