The Expression Of Tr?1 In The Cerebellum Of Mice And The Effect Of Tr?1 E403X Mutation On The Cerebellum

Thyroid hormone(TH)and Thyroid hormone receptors(TR)plays a crucial role in the development of the central nervous system,which including the cerebellum.The development of cerebellum is in the late stage of central nervous system.In mice,the development of cerebellum is mainly within 2-3 weeks after birth.Cerebellum is an important target organ to study the effect of TH on the development of central nervous system.Hypothyroidism resulted in increased neuronal death in the inner granular cell layer of the cerebellum,prolonged duration of the outer granular cell layer,and affected migration of the granule cells and dendritic formation of Purkinje cells.The thyroid hormone can be given to mice within two weeks of birth to prevent the occurrence of these morphological abnormalities.The cerebellum of mice with thyroid hormone resistance syndrome(RTH)caused by TR?1 was similar to that of hypothyroidism mice.And the complete knockout of TR?1 receptor could restore some morphologic abnormalities caused by hypothyroidism.At present,it is believed that the mutated TR?1can not bind to TH normally,which leads to the inhibition of the transcription initiation of the target gene,and a similar result to hypothyroidism.However,the specific mechanism remains to be further studied.The present study deals with the development of cerebellum in mice at different stages,the expression of TR?1 in the developing cerebellum and the expression of TR?1 in cerebellum.The effects of E403 X mutation on the cerebellum of mice were preliminarily studied,which laid a good foundation for the further study of the mechanism of TH and TR on the cerebellum of mice.Methods: Development of cerebellum of C57BL6 mice was studied by Nissl staining in mice of E18.5,P0,P3,P5,P7,P14.RNAscope technique was used to study the expression of TR?1 in the cerebellum of E18.5,P0,P3,P5,P7,P14,P56 mice.In order to study the effect of TR?1 mutation on cerebellum development and function in mice,we made the corresponding TR?1 E403 X mutant mice according to the first case of RTH?.The effect of TR?1 E403 X mutation on cerebellum development in mice was studied by Nissl staining to of 3-week-old homozygous mice and(homozygous mice could only survive about 3 weeks after birth),3-weeks-old,6-weeks-old,18-weeks-old heterozygous mice and 3-weeks-old,6-weeks-old,18-weeks-old wild-type mice.Gait of 6-week-old heterozygous mutant mice and wild-type mice was studied by gait detection technique to evaluate the effect of TR?1 E403 X mutation on cerebellum function of mice.Results: 1.The volume and area of cerebellum of mice increased rapidly after birth.2.In E18.5,TR?1 had been expressed all over mouse cerebellum.In P7,the expression of TR?1 decreased rapidly in Purkinje cells.In P14,the expression of TR?1 had begun to decrease to about P14 in granule cells.And in P56,TR?1 hardly expressed in cerebellum.3.The migration of the outer granular cells in the cerebellum of TR?1 E403 X homozygous mice had not completed at 3 weeks after birth.In heterozygous mice,it had almost completed,and in wild type mice,it had totally completed.4.The walking speed of female and male heterozygous mice at the age of 6 weeks was significantly slower than wild type mice of the same age and same sex.The body movement speed of female and male heterozygous mice at 6 weeks was significantly slower than wild type mice of the same age and sex.The stride of female and male heterozygous mice at the age of 6weeks was significantly shorter than wild type mice of the same age and sex.Conclusion: 1.The development of cerebellum in mice was mainly concentrated in the first two weeks after birth.2.The expression of TR?1 in the cerebellum of mice was time-specific,and the expression peak of TR?1 in granule cells was the same as the development peak of the cerebellum of mice.The expression of TR?1 decreased rapidly after the development of the cerebellum of mice.3.In Purkinje cells,the expression of TR?1 mainly concentrated in the first week after birth.4.The mutation of TR?1 E403 X will affect the neuronal migration during the development of cerebellum of mice.5.The mutation of TR?1 E403 X will damage the gait of the mice,which may be the consequence of affecting the development of the cerebellum of mice.