Elucidating the Role of Epithelial PCP signaling in SGN Axon Guidance in the Cochlea
阐明上皮 PCP 信号传导在耳蜗 SGN 轴突引导中的作用
基本信息
- 批准号:10739288
- 负责人:
- 金额:$ 3.63万
- 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:2022-07-01 至 2025-06-30
- 项目状态:未结题
- 来源:
- 关键词:Acoustic TraumaAdhesionsAfferent NeuronsAllelesApicalAuditoryAxonBehaviorBindingBiological AssayBrainCRISPR/Cas technologyCell AdhesionCell Adhesion MoleculesCell-Cell AdhesionCharacteristicsChimeric ProteinsCochleaCochlear nucleusCoculture TechniquesCongenital AbnormalityCytoskeletonDataDevelopmentDevelopmental ProcessDiseaseDissociationEmbryoEpitheliumFc domainFoundationsGenesGoalsGuanosine TriphosphateGuanosine Triphosphate PhosphohydrolasesHairHair CellsHearingImmunoglobulinsImmunohistochemistryInner Hair CellsIntercellular JunctionsKnock-outKnockout MiceKnowledgeLabelLabyrinthLigandsMammalsMediatingMembraneMolecularMorphogenesisMorphologyMusNatural regenerationNatureNervous SystemNeuronsNoiseOrganOrgan of CortiOuter Hair CellsPainPathway interactionsPatternPeripheralPillar CellPlayPropertyProteinsRegulationReporterRoleSensorySensory DisordersSignal TransductionStereotypingSupporting CellTestingTissue imagingTissuesTransgenic OrganismsWorkapical membraneaxon guidancebasecell behaviorconditional knockoutemx2 proteinexperimental studyhearing impairmenthearing restorationhindbraininner ear developmentinsightloss of functionmembermutantnectinnerve supplynervous system developmentnew therapeutic targetnovelnovel therapeutic interventionnoxacusisplanar cell polaritypolarized cellreceptorrepairedrho GTP-Binding Proteinssoundspiral gangliontherapeutic targettissue fixingtransmission processubiquitin-protein ligase
项目摘要
Our sense of hearing is critically dependent on the spiral ganglion neurons (SGNs), which connect the sound
receptors in the organ of Corti (OC) to the cochlear nuclei of the hindbrain. During development, SGNs establish
stereotyped innervation patterns with specific hair cell targets in the OC. Type I SGNs innervate inner hair cells
(IHCs) to transmit sound signals, while type II SGNs (SGNIIs) innervate outer hair cells (OHCs) to detect acoustic
trauma. Despite their essential functions in hearing, our understanding of the molecular mechanisms that
mediate wiring of the auditory periphery is still fragmentary.
It has been shown recently that guidance of SGNII peripheral projections is regulated by the Planar Cell
Polarity (PCP) pathway. Intercellular PCP signaling mediates polarized cell behaviors within the plane of a tissue
in a plethora of developmental processes. In the wild-type OC, SGNII afferents make a characteristic 90-degree
turn toward the base of the cochlea and innervate multiple OHCs. In several PCP mutants, SGNII afferents turn
randomly towards either the cochlear base or the apex. Although it has been shown that PCP proteins localize
asymmetrically to supporting cell (SC)-SC junctions and act in the cochlear epithelium to guide SGNII afferents,
the underlying mechanisms are currently unknown. Based on a strong foundation of preliminary data, we will
test the hypothesis that PCP signaling regulates multiple downstream effectors including adhesion molecules
and Rho GTPases to influence cell adhesion and the cytoskeleton in SCs, which serve as intermediate targets
of SGNIIs. Specifically, we found that PCP signaling regulates the localization of Nectin3, a member of the
immunoglobulin superfamily of adhesion molecules, in SCs. Moreover, our preliminary data have suggested that
the Rac GTPases are required in the cochlear epithelium for SGNII afferent guidance; however, their constitutive
activity was insufficient to direct SGNII afferents when PCP signaling is disrupted. To test our hypothesis, Aim
1 seeks to elucidate the role of Nectin3 in SGNII afferent turning. To this end, we have generated Nectin3
knockout mice using CRISPR-Cas9. We will characterize Nectin3 mutant alleles and analyze SGNII afferent
turning in Nectin3 knockout mutants. Additionally, to determine whether Nectin3-mediated heterophilic adhesion
between SCs and SGNII afferents plays a role in their turning direction, we will test the effect of soluble Nectin3
ecto domain-Fc fusion proteins on SGNII axon outgrowth and turning in cochlear explants and dissociated SGN
cultures. Aim 2 will further investigate mutual regulation between Rac signaling activity and asymmetric PCP
protein localization, using a newly generated transgenic Rac1 activity reporter line and Rac conditional knockout
mutants. Furthermore, we will also determine whether the E3 ubiquitin ligase POSH/Sh3rf1, a known Rac1
downstream effector, is involved in SGNII afferent guidance using loss-of-function perturbations. Together, the
proposed experiments will provide novel insights into how PCP signaling directs polarized cell behaviors and fill
our knowledge gaps about SGNII wiring mechanisms in the mammalian cochlea.
我们的听觉严重依赖于连接声音的螺旋神经节神经元(sgn)
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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Shaylyn Clancy其他文献
Shaylyn Clancy的其他文献
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{{ truncateString('Shaylyn Clancy', 18)}}的其他基金
Elucidating the Role of Epithelial PCP signaling in SGN Axon Guidance in the Cochlea
阐明上皮 PCP 信号传导在耳蜗 SGN 轴突引导中的作用
- 批准号:
10536706 - 财政年份:2022
- 资助金额:
$ 3.63万 - 项目类别:
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