Thyroid-stimulating hormone(TSH)is important for the thyroid gland,development,growth,and metabolism.Defects in TSH production or the thyrotrope cells within the pituitary gland cause congenital hypothyroidism(CH),res...Thyroid-stimulating hormone(TSH)is important for the thyroid gland,development,growth,and metabolism.Defects in TSH production or the thyrotrope cells within the pituitary gland cause congenital hypothyroidism(CH),resulting in growth retardation and neurocognitive impairment.While human TSH is known to display rhythmicity,the molecular mechanisms underlying the circadian regulation of TSH and the effects of TSH-thyroid hormone(TH)signaling on the circadian clock remain elusive.Here we show that TSH,thyroxine(T4),triiodothyronine(T3),and tshba display rhythmicity in both larval and adult zebrafish and tshba is regulated directly by the circadian clock via both E′-box and D-box.Zebrafish tshba^(−/−)mutants manifest congenital hypothyroidism,with the characteristics of low levels of T_(4)and T_(3)and growth retardation.Loss or overexpression of tshba alters the rhythmicity of locomotor activities and expression of core circadian clock genes and hypothalamic-pituitary-thyroid(HPT)axis-related genes.Furthermore,TSH-TH signaling regulates clock2/npas2 via the thyroid response element(TRE)in its promoter,and transcriptome analysis reveals extensive functions of Tshba in zebrafish.Together,our results demonstrate that zebrafish tshba is a direct target of the circadian clock and in turn plays critical roles in circadian regulation along with other functions.展开更多
基金supported by grants from the National Key Research and Development Program of China(2019YFA0802400)the National Natural Science Foundation of China(NSFC)(#31300969,#31961133026,#31871187)the Natural Science Foundation of Jiangsu Province(BK20130302),a Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions(PARD).
文摘Thyroid-stimulating hormone(TSH)is important for the thyroid gland,development,growth,and metabolism.Defects in TSH production or the thyrotrope cells within the pituitary gland cause congenital hypothyroidism(CH),resulting in growth retardation and neurocognitive impairment.While human TSH is known to display rhythmicity,the molecular mechanisms underlying the circadian regulation of TSH and the effects of TSH-thyroid hormone(TH)signaling on the circadian clock remain elusive.Here we show that TSH,thyroxine(T4),triiodothyronine(T3),and tshba display rhythmicity in both larval and adult zebrafish and tshba is regulated directly by the circadian clock via both E′-box and D-box.Zebrafish tshba^(−/−)mutants manifest congenital hypothyroidism,with the characteristics of low levels of T_(4)and T_(3)and growth retardation.Loss or overexpression of tshba alters the rhythmicity of locomotor activities and expression of core circadian clock genes and hypothalamic-pituitary-thyroid(HPT)axis-related genes.Furthermore,TSH-TH signaling regulates clock2/npas2 via the thyroid response element(TRE)in its promoter,and transcriptome analysis reveals extensive functions of Tshba in zebrafish.Together,our results demonstrate that zebrafish tshba is a direct target of the circadian clock and in turn plays critical roles in circadian regulation along with other functions.
