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
Sp7/Osterix as a zinc finger transcription factor is expressed specifically in osteoblasts.Embryonic lethality of Sp7 knockout mice,however,has prevented from examining the functions of Sp7 in osteoblast and bone form...Sp7/Osterix as a zinc finger transcription factor is expressed specifically in osteoblasts.Embryonic lethality of Sp7 knockout mice,however,has prevented from examining the functions of Sp7 in osteoblast and bone formation in live animals.Here we used TALEN,a versatile genome-editing tool,to generate one zebrafish sp7 mutant line.Homozygous sp7-/- mutant zebrafish are able to survive to adulthood.Alizarin Red staining and Micro-CT analysis showed that sp7-/- larvae and adult fish fail to develop normal opercula,and display curved tail fins and severe craniofacial malformation,while Alcian Blue staining showed no obvious cartilage defects in sp7-/- fish.Quantitative RT-PCR showed that a number of osteoblast markers including spp1,phex,col1 ala,and col1a1 b are significantly down-regulated in sp7-/- fish.Furthermore,col10a1 a,whose ortholog is the cartilage marker in mice,was shown to be a novel downstream gene of Sp7 as an osteoblast marker in zebrafish.Together,these results suggest that Sp7 is required for zebrafish bone development and zebrafish sp7 mutants provide animal models for investigating novel aspects of bone development.展开更多
Attention deficit hyperactivity disorder(ADHD)is one of the most prevalent psychiatric disorders in children,and ADHD patients always display circadian abnormalities.While,the ADHD drugs currently used in clinic have ...Attention deficit hyperactivity disorder(ADHD)is one of the most prevalent psychiatric disorders in children,and ADHD patients always display circadian abnormalities.While,the ADHD drugs currently used in clinic have strong side effects,such as psychosis,allergic reactions,and heart problems.Here,we demonstrated carbon dots derived from the ascorbic acid(VCDs)could strongly rescue the hyperactive and impulsive behaviour of a zebrafish ADHD disease model caused by per1b mutation.VCDs prolonged the circadian period of zebrafish for more than half an hour.In addition,the amplitude and circadian phase were also changed.The dopamine level was specifically increased,which may be caused by stimulation of the dopaminergic neuron development in the midbrain.Notably,it was found that the serotonin level was not altered by VCDs treatments.Also,the gene transcriptome effects of VCDs were discussed in present work.Our results provided the dynamic interactions of carbon dots with circadian system and dopamine signaling pathway,which illustrates a potential application of degradable and bio-safe VCDs for the treatment of the attention deficient and hyperactive disorder through circadian intervention.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.
基金supported by the grants from National High Technology Research and Development Program of China (2011AA100402-2)the National Natural Science Foundation of China (NSFC) (31271356, 31030062, 81070455)+5 种基金National Basic Research Program of China (2012CB947600)the Jiangsu Distinguished Professorship Program (SR13400111)the Natural Science Foundation of Jiangsu Province (BK2012052)the Priority Academic Program Development (PAPD) of Jiangsu Higher Education Institutions (YX13400214)the High-Level Innovative Team of Jiangsu Provincethe ‘‘333” project of Jiangsu Province (BRA2015328)
文摘Sp7/Osterix as a zinc finger transcription factor is expressed specifically in osteoblasts.Embryonic lethality of Sp7 knockout mice,however,has prevented from examining the functions of Sp7 in osteoblast and bone formation in live animals.Here we used TALEN,a versatile genome-editing tool,to generate one zebrafish sp7 mutant line.Homozygous sp7-/- mutant zebrafish are able to survive to adulthood.Alizarin Red staining and Micro-CT analysis showed that sp7-/- larvae and adult fish fail to develop normal opercula,and display curved tail fins and severe craniofacial malformation,while Alcian Blue staining showed no obvious cartilage defects in sp7-/- fish.Quantitative RT-PCR showed that a number of osteoblast markers including spp1,phex,col1 ala,and col1a1 b are significantly down-regulated in sp7-/- fish.Furthermore,col10a1 a,whose ortholog is the cartilage marker in mice,was shown to be a novel downstream gene of Sp7 as an osteoblast marker in zebrafish.Together,these results suggest that Sp7 is required for zebrafish bone development and zebrafish sp7 mutants provide animal models for investigating novel aspects of bone development.
基金the National Natural Science Foundation of China(Nos.31671216,81871193,51725204,21771132,51972216,and 52041202)the National MCF Energy R&D Program of China(No.2018YFE0306105)+8 种基金the National Key R&D Program of China(Nos.2020YFA0406104 and 2020YFA0406101)Innovative Research Group Project of the National Natural Science Foundation of China(No.51821002)Natural Science Foundation of Jiangsu Province(No.BK20190041)National College Students Innovation and Entrepreneurship Training Program(No.201710285042Z)Suzhou Scientific Program(No.SS202074)Key R&D program of Ningxia Hui Autonomous Region(No.2022BEG02006)Ningxia Autonomous Region flexible introduction of science and technology innovation team(No.2021RXTDLX08)Agricultural science and technology innovation project of Suzhou Science and Technology Development Plan(No.SNG2020074)Collaborative Innovation Center of Suzhou Nano Science&Technology,the 111 Project,and Suzhou Key Laboratory of Functional Nano&Soft Materials.
文摘Attention deficit hyperactivity disorder(ADHD)is one of the most prevalent psychiatric disorders in children,and ADHD patients always display circadian abnormalities.While,the ADHD drugs currently used in clinic have strong side effects,such as psychosis,allergic reactions,and heart problems.Here,we demonstrated carbon dots derived from the ascorbic acid(VCDs)could strongly rescue the hyperactive and impulsive behaviour of a zebrafish ADHD disease model caused by per1b mutation.VCDs prolonged the circadian period of zebrafish for more than half an hour.In addition,the amplitude and circadian phase were also changed.The dopamine level was specifically increased,which may be caused by stimulation of the dopaminergic neuron development in the midbrain.Notably,it was found that the serotonin level was not altered by VCDs treatments.Also,the gene transcriptome effects of VCDs were discussed in present work.Our results provided the dynamic interactions of carbon dots with circadian system and dopamine signaling pathway,which illustrates a potential application of degradable and bio-safe VCDs for the treatment of the attention deficient and hyperactive disorder through circadian intervention.