在肢体发育中,Sonic hedgehog(SHH)蛋白作为极化区(the zone of polarizing actiVity,ZPA)的调节因子,发挥着十分重要的作用。然而SHH是如何沿着肢体的前后轴发挥调控作用的还不是很清楚。最近的报道表明SHH主要是通过阻止转录因子GLI3...在肢体发育中,Sonic hedgehog(SHH)蛋白作为极化区(the zone of polarizing actiVity,ZPA)的调节因子,发挥着十分重要的作用。然而SHH是如何沿着肢体的前后轴发挥调控作用的还不是很清楚。最近的报道表明SHH主要是通过阻止转录因子GLI3裂解成抑制形式发挥作用,而后者也能够关闭SHH靶基因的表达。GLI基因家族的成员编码含有锌指结构的转录因子,主要对SHH的靶基因发挥调节作用。现就GLI基因在肢体发育中的表达特点及其临床意义进行综述。展开更多
Limb loss shows recurrent phenotypic evolution across squamate lineages.Here,based on three de novo-assembled genomes of limbless lizards from different lineages,we showed that divergence of conserved non-coding eleme...Limb loss shows recurrent phenotypic evolution across squamate lineages.Here,based on three de novo-assembled genomes of limbless lizards from different lineages,we showed that divergence of conserved non-coding elements(CNEs)played an important role in limb development.These CNEs were associated with genes required for limb initiation and outgrowth,and with regulatory signals in the early stage of limb development.Importantly,we identified the extensive existence of insertions and deletions(In Dels)in the CNEs,with the numbers ranging from 111 to 756.Most of these CNEs with In Dels were lineagespecific in the limbless squamates.Nearby genes of these In Del CNEs were important to early limb formation,such as Tbx4,Fgf10,and Gli3.Based on functional experiments,we found that nucleotide mutations and In Dels both affected the regulatory function of the CNEs.Our study provides molecular evidence underlying limb loss in squamate reptiles from a developmental perspective and sheds light on the importance of regulatory element In Dels in phenotypic evolution.展开更多
Background: The 2 most cited sports injury prevention research frameworks incorporate intervention development, yet little guidance is available in the sports science literature on how to undertake this complex proces...Background: The 2 most cited sports injury prevention research frameworks incorporate intervention development, yet little guidance is available in the sports science literature on how to undertake this complex process. This paper presents a generalizable process for developing implementable sports injury prevention interventions, including a case study applying the process to develop a lower limb injury prevention exercise training program(Footy First) for community Australian football.Methods: The intervention development process is underpinned by 2 complementary premises:(1) that evidence-based practice integrates the best available scientific evidence with practitioner expertise and end user values and(2) that research evidence alone is insufficient to develop implementable interventions.Results: The generalizable 6-step intervention development process involves(1) compiling research evidence, clinical experience, and knowledge of the implementation context;(2) consulting with experts;(3) engaging with end users;(4) testing the intervention;(5) using theory; and(6)obtaining feedback from early implementers. Following each step, intervention content and presentation should be revised to ensure that the final intervention includes evidence-informed content that is likely to be adopted, properly implemented, and sustained over time by the targeted intervention deliverers. For Footy First, this process involved establishing a multidisciplinary intervention development group, conducting 2targeted literature reviews, undertaking an online expert consensus process, conducting focus groups with program end users, testing the program multiple times in different contexts, and obtaining feedback from early implementers of the program.Conclusion: This systematic yet pragmatic and iterative intervention development process is potentially applicable to any injury prevention topic across all sports settings and levels. It will guide researchers wishing to undertake intervention development.展开更多
The overlapping roles of Hippo and Hedgehog signaling in biological functions and diseases prompt us to inves-tigate their potential interactions.Activation of Hippo signaling enhances the transcriptional output of He...The overlapping roles of Hippo and Hedgehog signaling in biological functions and diseases prompt us to inves-tigate their potential interactions.Activation of Hippo signaling enhances the transcriptional output of Hedgehog signaling,and the role of Hippo signaling in regulating Hedgehog signaling relies on the Hippo pathway key effector,Taz.Interestingly,Taz exhibits a gradient expression across the posterior-to-anterior of limb bud mesoderms,similar to Sonic hedgehog(Shh).Importantly,Taz drives PKA to phosphorylate Gli3,resulting in the Gli3 processing into its repressor and attenuation of Hedgehog signaling in the Shh-independent manner.Specifically,Taz deletion in mouse embryonic limb bud mesenchyme not only enhances the Hedgehog signaling but partially restores the phenotypes from Shh deletion in causing severe defects of anteroposterior patterning and digit number and identity.Together,these results uncover Taz-dependent Gli3 processing as a hitherto uncharacterized mechanism controlling Hedgehog signaling,highlighting its cross-regulation by Hippo signaling.展开更多
Understanding limb development not only gives insights into the outgrowth and differentiation of the limb,but also has clinical relevance.Limb development begins with two paired limb buds(forelimb and hindlimb buds),w...Understanding limb development not only gives insights into the outgrowth and differentiation of the limb,but also has clinical relevance.Limb development begins with two paired limb buds(forelimb and hindlimb buds),which are initially undifferentiated mesenchymal cells tipped with a thickening of the ectoderm,termed the apical ectodermal ridge(AER).As a transitional embryonic structure,the AER undergoes four stages and contributes to multiple axes of limb development through the coordination of signalling centres,feedback loops,and other cell ac-tivities by secretory signalling and the activation of gene expression.Within the scope of proximodistal pattering,it is understood that while fibroblast growth factors(FGFs)function sequentially over time as primary components of the AER signalling process,there is still no consensus on models that would explain proximodistal patterning itself.In anteroposterior pattermning,the AER has a dual-direction regulation by which it promotes the sonic hedgehog(Shh)gene expression in the zone of polarizing activity(ZPA)for proliferation,and inhibits Shh expression in the anterior mesenchyme.In dorsoventral patterming,the AER activates Engrailed-1(En1)expression,and thus represses Wnt family member 7a(Wnt7a)expression in the ventral ectoderm by the expression of Fgfs,Sp6/8,and bone morpho-genetic protein(Bmp)genes.The AER also plays a vital role in shaping the individual digits,since levels of Fgf4/8 and Bmps expressed in the AER affect digit patterning by controlling apoptosis.In summary,the knowledge of crosstalk within AER among the three main axes is essential to understand limb growth and pattern fomation,as the development of its areas proceeds simultaneously.展开更多
文摘在肢体发育中,Sonic hedgehog(SHH)蛋白作为极化区(the zone of polarizing actiVity,ZPA)的调节因子,发挥着十分重要的作用。然而SHH是如何沿着肢体的前后轴发挥调控作用的还不是很清楚。最近的报道表明SHH主要是通过阻止转录因子GLI3裂解成抑制形式发挥作用,而后者也能够关闭SHH靶基因的表达。GLI基因家族的成员编码含有锌指结构的转录因子,主要对SHH的靶基因发挥调节作用。现就GLI基因在肢体发育中的表达特点及其临床意义进行综述。
基金the Strategic Priority Research Program of Chinese Academy of Sciences(XDB31000000)the National Natural Science Foundation of China(32220103004,32000296)+2 种基金the Second Tibetan Plateau Scientific Expedition and Research Program(2019QZKK0501)the International Partnership Program of Chinese Academy of Sciences(151751KYSB20190024)the Sichuan Science and Technology Program(2021JDJQ0002)。
文摘Limb loss shows recurrent phenotypic evolution across squamate lineages.Here,based on three de novo-assembled genomes of limbless lizards from different lineages,we showed that divergence of conserved non-coding elements(CNEs)played an important role in limb development.These CNEs were associated with genes required for limb initiation and outgrowth,and with regulatory signals in the early stage of limb development.Importantly,we identified the extensive existence of insertions and deletions(In Dels)in the CNEs,with the numbers ranging from 111 to 756.Most of these CNEs with In Dels were lineagespecific in the limbless squamates.Nearby genes of these In Del CNEs were important to early limb formation,such as Tbx4,Fgf10,and Gli3.Based on functional experiments,we found that nucleotide mutations and In Dels both affected the regulatory function of the CNEs.Our study provides molecular evidence underlying limb loss in squamate reptiles from a developmental perspective and sheds light on the importance of regulatory element In Dels in phenotypic evolution.
基金funded by an National Health and Medical Research Council (NHMRC) Partnership Project Grant (ID: 565907) which included additional support (both cash and in-kind) from the following project partner agencies: the Australian Football League Victorian Health Promotion Foundation+7 种基金 New South Wales Sporting Injuries Committee JLT Sport, a division of Jardine Lloyd Thompson Australia Pty Ltd. Sport and Recreation Victoria, Department of Transport, Planning and Local Infrastructure and Sports Medicine Australia- National and Victorian Branchessupported by an NHMRC Principal Research Fellowship (APP1058737)supported by an NHMRC Career Development Fellowship (APP1048731)supported by a NHMRC Practitioner fellowship (APP1058493)Research Fellowships funded through the major NHMRC Partnership Project Grant
文摘Background: The 2 most cited sports injury prevention research frameworks incorporate intervention development, yet little guidance is available in the sports science literature on how to undertake this complex process. This paper presents a generalizable process for developing implementable sports injury prevention interventions, including a case study applying the process to develop a lower limb injury prevention exercise training program(Footy First) for community Australian football.Methods: The intervention development process is underpinned by 2 complementary premises:(1) that evidence-based practice integrates the best available scientific evidence with practitioner expertise and end user values and(2) that research evidence alone is insufficient to develop implementable interventions.Results: The generalizable 6-step intervention development process involves(1) compiling research evidence, clinical experience, and knowledge of the implementation context;(2) consulting with experts;(3) engaging with end users;(4) testing the intervention;(5) using theory; and(6)obtaining feedback from early implementers. Following each step, intervention content and presentation should be revised to ensure that the final intervention includes evidence-informed content that is likely to be adopted, properly implemented, and sustained over time by the targeted intervention deliverers. For Footy First, this process involved establishing a multidisciplinary intervention development group, conducting 2targeted literature reviews, undertaking an online expert consensus process, conducting focus groups with program end users, testing the program multiple times in different contexts, and obtaining feedback from early implementers of the program.Conclusion: This systematic yet pragmatic and iterative intervention development process is potentially applicable to any injury prevention topic across all sports settings and levels. It will guide researchers wishing to undertake intervention development.
基金supported by National Basic Research Program of China(No.2018YFC1004404)National Natural Science Foundation of China(Nos.31071292,32170841,31271561,31571493,81741043,31871395,and 31801207).
文摘The overlapping roles of Hippo and Hedgehog signaling in biological functions and diseases prompt us to inves-tigate their potential interactions.Activation of Hippo signaling enhances the transcriptional output of Hedgehog signaling,and the role of Hippo signaling in regulating Hedgehog signaling relies on the Hippo pathway key effector,Taz.Interestingly,Taz exhibits a gradient expression across the posterior-to-anterior of limb bud mesoderms,similar to Sonic hedgehog(Shh).Importantly,Taz drives PKA to phosphorylate Gli3,resulting in the Gli3 processing into its repressor and attenuation of Hedgehog signaling in the Shh-independent manner.Specifically,Taz deletion in mouse embryonic limb bud mesenchyme not only enhances the Hedgehog signaling but partially restores the phenotypes from Shh deletion in causing severe defects of anteroposterior patterning and digit number and identity.Together,these results uncover Taz-dependent Gli3 processing as a hitherto uncharacterized mechanism controlling Hedgehog signaling,highlighting its cross-regulation by Hippo signaling.
基金Key Research and Development Project of Shandong Province(No.2017G006043),China。
文摘Understanding limb development not only gives insights into the outgrowth and differentiation of the limb,but also has clinical relevance.Limb development begins with two paired limb buds(forelimb and hindlimb buds),which are initially undifferentiated mesenchymal cells tipped with a thickening of the ectoderm,termed the apical ectodermal ridge(AER).As a transitional embryonic structure,the AER undergoes four stages and contributes to multiple axes of limb development through the coordination of signalling centres,feedback loops,and other cell ac-tivities by secretory signalling and the activation of gene expression.Within the scope of proximodistal pattering,it is understood that while fibroblast growth factors(FGFs)function sequentially over time as primary components of the AER signalling process,there is still no consensus on models that would explain proximodistal patterning itself.In anteroposterior pattermning,the AER has a dual-direction regulation by which it promotes the sonic hedgehog(Shh)gene expression in the zone of polarizing activity(ZPA)for proliferation,and inhibits Shh expression in the anterior mesenchyme.In dorsoventral patterming,the AER activates Engrailed-1(En1)expression,and thus represses Wnt family member 7a(Wnt7a)expression in the ventral ectoderm by the expression of Fgfs,Sp6/8,and bone morpho-genetic protein(Bmp)genes.The AER also plays a vital role in shaping the individual digits,since levels of Fgf4/8 and Bmps expressed in the AER affect digit patterning by controlling apoptosis.In summary,the knowledge of crosstalk within AER among the three main axes is essential to understand limb growth and pattern fomation,as the development of its areas proceeds simultaneously.
