Mitochondrial dysfunction is a critical factor leading to a wide range of clinically heterogeneous and often severe disorders due to its central role in generating cellular energy.Mutations in the TUFM gene are known ...Mitochondrial dysfunction is a critical factor leading to a wide range of clinically heterogeneous and often severe disorders due to its central role in generating cellular energy.Mutations in the TUFM gene are known to cause combined oxidative phosphorylation deficiency 4(COXPD4),a rare mitochondrial disorder characterized by a comprehensive quantitative deficiency in mitochondrial respiratory chain(MRC)complexes.The development of a reliable animal model for COXPD4 is crucial for elucidating the roles and mechanisms of TUFM in disease pathogenesis and benefiting its medical management.In this study,we construct a zebrafish tufm−/−mutant that closely resembles the COXPD4 syndrome,exhibiting compromised mitochondrial protein translation,dysfunctional mitochondria with oxidative phosphorylation defects,and significant metabolic suppression of the tricarboxylic acid cycle.Leveraging this COXPD4 zebrafish model,we comprehensively validate the clinical relevance of TUFM mutations and identify probucol as a promising therapeutic approach for managing COXPD4.Our data offer valuable insights for understanding mitochondrial diseases and developing effective treatments.展开更多
Clathrin-mediated endocytosis has been implicated in various physiological processes,including nutrient uptake,signal transduction,synaptic vesicle recycling,maintenance of cell polarity,and antigen presentation.Despi...Clathrin-mediated endocytosis has been implicated in various physiological processes,including nutrient uptake,signal transduction,synaptic vesicle recycling,maintenance of cell polarity,and antigen presentation.Despite prior knowledge of its importance as a key regulator in promoting clathrin-mediated endocytosis,the physiological function of α-and γ-adaptin binding protein(aagab)remains elusive.In this study,we investigate the biological function of aagab during zebrafish development.We establish a loss-of-function mutant of aagab in zebrafish,revealing impaired swimming and early larval mortality.Given the high expression level of aagab in the brain,we probe into its physiological role in the nervous system.aagab mutants display subdued calcium responses and local field potential in the optic tectal neurons,aligning with reduced neurotransmitter release(e.g.,norepinephrine)in the tectal neuropil of aagab mutants.Overexpressing aagab mRNA or nervous stimulant treatment in mutants restores neurotransmitter release,calcium responses,swimming ability,and survival.Furthermore,our observations show delayed release of FM 1-43 in AAGAB knockdown differentiated neuroblastoma cells,pointing towards a probable link to defective clathrin-mediated synaptic vesicle recycling.In conclusion,our study underscores the significance of Aagab in neurobiology and suggests its potential impacts on neurological disorders.展开更多
The zebrafish sensory posterior lateral line(pLL)has become an attractive model for studying collective cell migration and cell morphogenesis.Recent studies have indicated that chemokine,Wnt/β-catenin,Fgf,and Delta-N...The zebrafish sensory posterior lateral line(pLL)has become an attractive model for studying collective cell migration and cell morphogenesis.Recent studies have indicated that chemokine,Wnt/β-catenin,Fgf,and Delta-Notch signaling pathways participate in regulating pLL development.However,it remains unclear whether TGFβsignaling pathway is involved in pLL development.Here we report a critical role of TGFβ1 in regulating morphogenesis of the pLL primordium(pLLP).The tgfβ1a gene is abundantly expressed in the lateral line primordium.Knockdown or knockout of tgfβ1a leads to a reduction of neuromast number,an increase of inter-neuromast distance,and a reduced number of hair cells.The aberrant morphogenesis in embryos depleted of tgfβ1a correlates with the reduced expression of atoh1a,deltaA,and n-cadherin/cdh2,which are known important regulators of the pLLP morphogenesis.Like tgfβ1a depletion,knockdown of smad5 that expresses in the pLLP,affects pLLP development whereas overexpression of a constitutive active Smad5 isoform rescues the defects in embryos depleted of tgfβ1a,indicating that Smad5 mediates tgfβ1a function in pLLP development.Therefore,TGFβ/Smad5 signaling plays an important role in the zebrafish lateral line formation.展开更多
Intraluminal lymphatic valves(LVs)and lymphovenous valves(LVs)are critical to ensure the unidirectional flow of lymphatic fluid.Morphological abnormalities in these valves always cause lymph or blood reflux,and result...Intraluminal lymphatic valves(LVs)and lymphovenous valves(LVs)are critical to ensure the unidirectional flow of lymphatic fluid.Morphological abnormalities in these valves always cause lymph or blood reflux,and result in lymphedema.展开更多
Prpf4 （pre-mRNA processing factor 4）, a key component of spliceosome, plays critical roles in pre-mRNA splicing and its mutations result in retinitis pigmentosa due to photoreceptor defects. In this study, we charac...Prpf4 （pre-mRNA processing factor 4）, a key component of spliceosome, plays critical roles in pre-mRNA splicing and its mutations result in retinitis pigmentosa due to photoreceptor defects. In this study, we characterized a zebrafish prpf4t243 mutant harboring a Tol2 transposon-based gene trap cassette in the third intron of the prpf4 gene. Cells in the brain and spinal cord gradually undergo p53-dependent apoptosis after 28 hpf in prpf4t243 mutants, suggesting that a widespread function of prpf4 in neural cell survival. In addition, prpf4 is essential for survival of posterior lateral line primordial （pLLP） cells, prpf4 deficiency perturbs Fgf, Wnt/β-catenin and chemokine signaling pathways and impairs pLLP migration. RNA-Seq analysis suggests that prpf4 deficiency may impair spliceosome assembly, leading to compensatory upregulation of core spliceosomal genes and alteration of pre-mRNA splicing. Taken together, our studies uncover an essential role of prpf4 in pre-mRNA splicing, cell survival and pLLP migration.展开更多
基金supported by the National Natural Science Foundation of China(#92254302 and#32293202 to S.J.)National Key Research and Development(#2019YFA0801403 to S.J.).
文摘Mitochondrial dysfunction is a critical factor leading to a wide range of clinically heterogeneous and often severe disorders due to its central role in generating cellular energy.Mutations in the TUFM gene are known to cause combined oxidative phosphorylation deficiency 4(COXPD4),a rare mitochondrial disorder characterized by a comprehensive quantitative deficiency in mitochondrial respiratory chain(MRC)complexes.The development of a reliable animal model for COXPD4 is crucial for elucidating the roles and mechanisms of TUFM in disease pathogenesis and benefiting its medical management.In this study,we construct a zebrafish tufm−/−mutant that closely resembles the COXPD4 syndrome,exhibiting compromised mitochondrial protein translation,dysfunctional mitochondria with oxidative phosphorylation defects,and significant metabolic suppression of the tricarboxylic acid cycle.Leveraging this COXPD4 zebrafish model,we comprehensively validate the clinical relevance of TUFM mutations and identify probucol as a promising therapeutic approach for managing COXPD4.Our data offer valuable insights for understanding mitochondrial diseases and developing effective treatments.
基金supported by the National Natural Science Foundation of China(#92254302,#32293202,#2019YFA0801400 to S.J.,and#31988101 to A.M.).
文摘Clathrin-mediated endocytosis has been implicated in various physiological processes,including nutrient uptake,signal transduction,synaptic vesicle recycling,maintenance of cell polarity,and antigen presentation.Despite prior knowledge of its importance as a key regulator in promoting clathrin-mediated endocytosis,the physiological function of α-and γ-adaptin binding protein(aagab)remains elusive.In this study,we investigate the biological function of aagab during zebrafish development.We establish a loss-of-function mutant of aagab in zebrafish,revealing impaired swimming and early larval mortality.Given the high expression level of aagab in the brain,we probe into its physiological role in the nervous system.aagab mutants display subdued calcium responses and local field potential in the optic tectal neurons,aligning with reduced neurotransmitter release(e.g.,norepinephrine)in the tectal neuropil of aagab mutants.Overexpressing aagab mRNA or nervous stimulant treatment in mutants restores neurotransmitter release,calcium responses,swimming ability,and survival.Furthermore,our observations show delayed release of FM 1-43 in AAGAB knockdown differentiated neuroblastoma cells,pointing towards a probable link to defective clathrin-mediated synaptic vesicle recycling.In conclusion,our study underscores the significance of Aagab in neurobiology and suggests its potential impacts on neurological disorders.
基金This work was financially supported by grants from the National Natural Science Foundation of China(#31371460)Major Science Programs of China(#2012CB945101 and#2011CB943800)。
文摘The zebrafish sensory posterior lateral line(pLL)has become an attractive model for studying collective cell migration and cell morphogenesis.Recent studies have indicated that chemokine,Wnt/β-catenin,Fgf,and Delta-Notch signaling pathways participate in regulating pLL development.However,it remains unclear whether TGFβsignaling pathway is involved in pLL development.Here we report a critical role of TGFβ1 in regulating morphogenesis of the pLL primordium(pLLP).The tgfβ1a gene is abundantly expressed in the lateral line primordium.Knockdown or knockout of tgfβ1a leads to a reduction of neuromast number,an increase of inter-neuromast distance,and a reduced number of hair cells.The aberrant morphogenesis in embryos depleted of tgfβ1a correlates with the reduced expression of atoh1a,deltaA,and n-cadherin/cdh2,which are known important regulators of the pLLP morphogenesis.Like tgfβ1a depletion,knockdown of smad5 that expresses in the pLLP,affects pLLP development whereas overexpression of a constitutive active Smad5 isoform rescues the defects in embryos depleted of tgfβ1a,indicating that Smad5 mediates tgfβ1a function in pLLP development.Therefore,TGFβ/Smad5 signaling plays an important role in the zebrafish lateral line formation.
基金This work is supported by the fundings from National Key Research and Development Program of China 2019YFA0801403Basic Science Center Program of NSFC 31988101.
文摘Intraluminal lymphatic valves(LVs)and lymphovenous valves(LVs)are critical to ensure the unidirectional flow of lymphatic fluid.Morphological abnormalities in these valves always cause lymph or blood reflux,and result in lymphedema.
基金financially supported by grants from the National Natural Science Foundation of China (Nos.31522035,31371460 and 31590832)
文摘Prpf4 （pre-mRNA processing factor 4）, a key component of spliceosome, plays critical roles in pre-mRNA splicing and its mutations result in retinitis pigmentosa due to photoreceptor defects. In this study, we characterized a zebrafish prpf4t243 mutant harboring a Tol2 transposon-based gene trap cassette in the third intron of the prpf4 gene. Cells in the brain and spinal cord gradually undergo p53-dependent apoptosis after 28 hpf in prpf4t243 mutants, suggesting that a widespread function of prpf4 in neural cell survival. In addition, prpf4 is essential for survival of posterior lateral line primordial （pLLP） cells, prpf4 deficiency perturbs Fgf, Wnt/β-catenin and chemokine signaling pathways and impairs pLLP migration. RNA-Seq analysis suggests that prpf4 deficiency may impair spliceosome assembly, leading to compensatory upregulation of core spliceosomal genes and alteration of pre-mRNA splicing. Taken together, our studies uncover an essential role of prpf4 in pre-mRNA splicing, cell survival and pLLP migration.
