Cadherin regulation of planar polarity
Cadherin regulation of planar polarity
批准号:
10711228
负责人:
Sara N Stahley
金额:
$41.19万
依托单位国家:
美国
项目类别:
财政年份:
2023
资助国家:
美国
项目状态:
未结题
起止时间:
2023-09-01 至 2028-06-30
关键词:
AdhesionsAdhesivesAnteriorBehavior ControlBiologicalBiological ModelsBiologyCadherinsCardiomyopathiesCell CommunicationCellsComplexCongenital Heart DefectsDefectDevelopmentDimerizationDiseaseEmbryoEpidermisFailureFamily memberGeneticGoalsHairHumanHuman DevelopmentImageImpairmentIntercellular JunctionsLabyrinthLateralMaintenanceMediatingMolecular BiologyMusMutationNeural Tube DefectsNeural tubeOrganPathogenicityPathway interactionsPatientsPatternProtein BiochemistryProteinsRegulationResearchRoleSignal PathwaySkinSpinal DysraphismTissuesWorkcell behaviorciliopathydevelopmental diseaseflygenetic approachhuman diseasein vivoinsightmolecular assembly/self assemblynovelplanar cell polarityprogramstrafficking
中文摘要
项目总结
英文摘要
PROJECT SUMMARY
During human development, cells interact with one another to drive collective and oriented cell behaviors that
control organ formation and tissue patterning. This coordination between neighboring cells is governed by planar
cell polarity (PCP), a signaling pathway conserved from flies to humans. An excellent example and functional
read-out of PCP, or collective polarization, is the ordered alignment of body hairs across the mammalian skin
along the anterior-posterior body axis. Genetic disruption of PCP components leads to severe developmental
disorders including cardiomyopathies, ciliopathies, and neural tube defects such as spina bifida. We lack a
detailed understanding for how targeting of the PCP pathway leads to developmental disorders. Importantly,
PCP disruption in mice that results in developmental defects and embryonic lethality also results in a failure to
properly pattern the embryonic epidermis, thus making the moue skin a suitable model system to study the
conserved biology of PCP. A hallmark feature of PCP is the asymmetric localization of core PCP proteins at cell
borders within a junctional complex organized via intercellular interactions of cadherin family member Celsr1.
Our long-term goal is to understand how Celsr1 adhesive interactions organize asymmetric cell junctions to
coordinate tissue polarity and how this molecular assembly is perturbed in human disease. The need to
understand how Celsr1 adhesion coordinates PCP asymmetry is underscored by the recent identification of
novel, predicted pathogenic, Celsr1 mutations in patients with neural tube and congenital heart defects.
Previously, our work revealed a role for cadherin-mediated dimerization, or lateral clustering, in the organization
of asymmetric PCP complexes. We hypothesize that Celsr1 cis-dimerization regulates trafficking of PCP
complexes during PCP establishment and that disease-associated Celsr1 mutations differentially impair Celsr1
adhesion and dimerization interactions to disrupt PCP during development. Using the mammalian skin as a
conduit for PCP function, along with molecular biology, protein biochemistry, advanced imaging and in vivo
genetic approaches, our research program will uncover the pathomechanisms of human disease-associated
Celsr1 mutations and reveal how Clesr1 dimerization regulates PCP establishment and maintenance. These
studies will provide novel insight into the mechanisms that regulate PCP and those that are perturbed in human
developmental disorders.
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会议论文
Celsr1-mediated planar cell polarity: defining the adhesive interface and mechanisms of asymmetry
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批准号:9328279
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项目类别:
-
资助金额:$5.67万
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财政年份:2017
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负责人:Sara N Stahley
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依托单位:
海外基金