Function and regulatory mechanisms of the Wnt5a-Ror morphogenetic pathway
Wnt5a-Ror形态发生途径的功能和调控机制
基本信息
- 批准号:10558623
- 负责人:
- 金额:$ 43.13万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-02-01 至 2027-01-31
- 项目状态:未结题
- 来源:
- 关键词:ActomyosinAddressAutomobile DrivingBehaviorBehavioralBinding ProteinsBiochemicalBiological AssayBiological ProcessBiomechanicsCanis familiarisCell Culture SystemCell surfaceCellsCharacteristicsClinicalComplementComplexCongenital AbnormalityCongenital DisordersCytoplasmCytoskeletonCytosolDNA Sequence AlterationDefectDevelopmentDiseaseDsh proteinElementsExhibitsFaceGeneticGoalsHumanKnock-outLigandsLimb structureMeasurementMediatingMorphogenesisMutationPathogenesisPathogenicityPathway interactionsPhenotypePhysiologicalPortraitsProcessProteinsRegulationReporterResearchRobinow syndromeRoleScaffolding ProteinSignal PathwaySignal TransductionStress FibersStructureTissuesTransducersVertebratesWNT5A genecell behaviorcell motilityexperimental studyhuman diseaseinsightinterestnovelpharmacologicreceptorthree dimensional cell culturetransmission process
项目摘要
Project Summary/Abstract
Wnt5a-Ror signaling is an evolutionarily conserved developmental signaling pathway that controls
morphogenetic cell and tissue behavior. Misregulation of the pathway in vertebrates results in profound tissue
elongation defects, including shortening and widening of the body axis, limbs, and face. In humans, mutations
in key nodes of the pathway, including the WNT5A ligand, the ROR2 and Frizzled (FZD2) co-receptors, and the
cytoplasmic signal transducers Dishevelled (DVL) 1 and DVL3, give rise to Robinow syndrome, a congenital
disorder with highly similar tissue elongation phenotypes. Notably, bulldogs exhibit similar physical
characteristics and carry a mutation in DVL2, analogous to the human mutations in DVL1 and DVL3, that reduces
its capacity to respond to Wnt5a-Ror signals. Despite its physiological and clinical importance, the biochemical
steps and cytoskeletal mechanisms that mediate Wnt5a-Ror signaling remain largely uncharacterized;
consequently, insights into the disease mechanism(s) driving Robinow syndrome are unknown. The overarching
goal of our research is to dissect Wnt5a-Ror pathway function and regulation at the biochemical, cellular and
organismal levels. Specifically, we ask in this proposal: 1) How does the Ror/FZD co-receptor complex transmit
Wnt5a signals at the cell surface, and how do pathogenic mutations in ROR2 alter receptor complex function?
2) How do Dvl scaffolding proteins relay Wnt5a-Ror signals in the cytosol, and how do mutations in human DVL1
and DVL3 and canine DVL2 disrupt DVL function? 3) How does the Wnt5a-Ror pathway engage the cytoskeleton
to alter cell behavior and biomechanics, and how do disease mutations in the pathway perturb these processes?
To address these questions, we have developed novel reporter assays that enable quantitative measurement of
Wnt5a-Ror signaling activity in live cells. We have also developed a highly physiological cell culture system in
which we can readily knock out and re-express proteins of interest at near-endogenous levels to rescue signaling.
Using this approach, we will conduct detailed ROR2 and DVL structure-function analyses to identify the structural
elements and mechanisms required for these proteins’ respective functions. These experiments will be
complemented by protein binding studies to define ROR2 and DVL protein interaction networks and how their
disruption contributes to disease pathogenesis. To elucidate the cell biological function of the pathway, we have
optimized 2D and 3D culture systems for cell behavioral analyses and identified a critical role for Wnt5a-Ror
signaling in controlling cell migration, stress fiber stabilization and actomyosin-based contractility. These
observations coincide with biochemical and subcellular localization changes in the RhoA-MLC-actomyosin
regulatory network. We will conduct pharmacological and genetic perturbation experiments to dissect the
function of this network in normal and pathogenic Wnt5a-Ror-directed cell behaviors. The successful completion
of this project will yield the first detailed mechanistic portrait of the Wnt5a-Ror signaling network and illuminate
the pathogenic mechanisms of Wnt5a-Ror-driven diseases.
项目总结/文摘
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Hsin-Yi Henry Ho其他文献
Hsin-Yi Henry Ho的其他文献
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{{ truncateString('Hsin-Yi Henry Ho', 18)}}的其他基金
Function and regulatory mechanisms of the Wnt5a-Ror morphogenetic pathway
Wnt5a-Ror形态发生途径的功能和调控机制
- 批准号:
10336968 - 财政年份:2022
- 资助金额:
$ 43.13万 - 项目类别:
Deciphering Wnt-Ror signaling in cytoskeletal regulation and tissue shape control
解读细胞骨架调节和组织形状控制中的 Wnt-Ror 信号传导
- 批准号:
10389593 - 财政年份:2016
- 资助金额:
$ 43.13万 - 项目类别:
Deciphering Wnt-Ror signaling in cytoskeletal regulation and tissue shape control
解读细胞骨架调节和组织形状控制中的 Wnt-Ror 信号传导
- 批准号:
9323512 - 财政年份:2016
- 资助金额:
$ 43.13万 - 项目类别:
Deciphering Wnt-Ror signaling in cytoskeletal regulation and tissue shape control
解读细胞骨架调节和组织形状控制中的 Wnt-Ror 信号传导
- 批准号:
9749980 - 财政年份:2016
- 资助金额:
$ 43.13万 - 项目类别:
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