Expression of sonic hedgehog regulates morphological changes of rat developing cerebellum in hypothyroidism.
Although thyroid hormones are crucial for cerebellar development, and several thyroid hormone-dependent genes are known to be correlated with morphological development of the cerebellum, the precise mechanisms of morphological cerebellar changes in hypothyroidism (HT) remain unknown. To investigate these mechanisms in experimental rat HT induced by the anti-thyroid drug methimazole (MMI-HT rat), we carried out gene expression analysis (sonic hedgehog (Shh), reelin, and Bax) using quantitative real-time PCR. Histological examination revealed cerebellar abnormalities, including reductions in the thickness of the molecular layer and delayed disappearance of the external granular layer (EGL), as well as excess bulges or sublobules in the internal granular layer (IGL). At Postnatal Day (P) 6, Shh expression in MMI-HT rat was comparable to that in controls, thus suggesting that Shh expression was sufficient to form the lobes in the initial phase. However, Shh expression decreased in the later phases, as compared with age-matched controls. This demonstrated that stronger and sustained signaling is necessary for partitioning of the cardinal lobes into lobes and sublobes. Although reelin expression was not clearly different from that in controls, Bax expression decreased at P 15. The attrition of Bax at P 15 as well as Shh in the later phase may be related to irregularities in the IGL and the relatively large numbers of internal granular cells. Taken together, these results suggest that Shh expression is related to the morphological cerebellar changes in experimental hypothyroidism and that sustained signaling by Shh may play a key role in normal development, particularly lobulation, in the cerebellum.
Hasebe
Miki
M
Department of Basic Veterinary Science, The United Graduate School of Veterinary Science, Yamaguchi University, Yamaguchi, Japan. mhasebe@its.jnj.com
Ohta
Etsuko
E
Imagawa
Tomohiro
T
Uehara
Masato
M
D000818:Animals; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics / Q000378:metabolism; D002531:Cerebellum / Q000002:abnormalities / Q000033:anatomy & histology* / Q000187:drug effects; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D007037:Hypothyroidism / Q000378:metabolism*; D008297:Male; D018811:Maternal Exposure; D008713:Methimazole / Q000633:toxicity; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D051381:Rats; D000091042:Reelin Protein; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
C494828:Bax protein, rat; D015816:Cell Adhesion Molecules, Neuronal; D016326:Extracellular Matrix Proteins; D053823:Hedgehog Proteins; D009419:Nerve Tissue Proteins; D000091042:Reelin Protein; C000717129:Reln protein, rat; D051028:bcl-2-Associated X Protein; D008713:Methimazole; D012697:Serine Endopeptidases