Intrinsic and extrinsic spindle orientation mechanisms in mammalian epidermis
哺乳动物表皮的内在和外在纺锤体定向机制
基本信息
- 批准号:10585931
- 负责人:
- 金额:$ 33.95万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-03-01 至 2026-01-31
- 项目状态:未结题
- 来源:
- 关键词:AblationAdherens JunctionAdhesionsAdhesivesAnaphaseApicalArchitectureBasal CellBehaviorBullaCadherinsCarcinomaCell DensityCell Fate ControlCell divisionCell-Cell AdhesionCell-Matrix JunctionCellsCommunitiesComplexCuesDaughterDefectDevelopmentDiseaseEctodermal DysplasiaEmbryoEpidermisEpidermolysis BullosaEpitheliumEquilibriumFocal AdhesionsGPSM1 geneGPSM2 geneGene ExpressionGene SilencingGenesGeneticGenetic ModelsGenetic TechniquesGoalsGrowthHemidesmosomesHomeostasisHomologous GeneHumanHyperplasiaImageIntegrinsIntrinsic factorJunctional Epidermolysis BullosaKnowledgeLabelLearningMalignant NeoplasmsMediatingMetaphaseMitosisModalityModelingMolecularMorphogenesisMutateMutationNatureOnline Mendelian Inheritance In ManOutcomePathogenesisPathologicPathway interactionsPatternPhenotypePhosphorylationPlayPositioning AttributeProcessProliferatingPropertyProteinsProteomicsRNA InterferenceResourcesRoleScaffolding ProteinShapesSignal PathwaySkinSkin AbnormalitiesStratificationStratified EpitheliumStratum BasaleStructureSyndromeTechniquesTimeTissuesVariantVinculinWorkafadinalpha catenincell cortexcleft lip and palatecohortex vivo imagingexhaustionexperimental studyflexibilityhuman diseasein vivoinnovationinsightknock-downloss of functionmechanotransductionmouse modelnectinparalogous geneprogenitorprotein protein interactionreal-time imagesresponseself-renewalskin disorderskin organogenesisstemstem cell divisionstem cellstelophasetherapy developmenttissue stresstooltreatment strategyultrasound
项目摘要
ABSTRACT
Proper control of stem cell division is critical for tissue morphogenesis and homeostasis. When dysregulated, it
can lead to hypoplasia and stem cell exhaustion on the one hand, or tissue overgrowth and cancer on the other.
But mitosis is more than simple proliferation, as cell division can be controlled not only in time but also in space.
Oriented cell divisions (OCDs) are an example of the latter, and for stem and progenitor cells, choices between
division axes can dictate cell fate outcomes and impact tissue architecture. In stratified epithelia such as the
epidermis, basal progenitors divide either within the plane of the epithelium, or perpendicular to it. Evidence
suggests that planar divisions are generally self-renewing symmetric cell divisions (SCDs) while perpendicular
divisions are differentiative asymmetric cell divisions (ACDs). Previous work from our lab has shown that ACDs
are directed by a complex of polarity and spindle orientation proteins—converging on the critical scaffolding
protein LGN (Gpsm2)—which localize asymmetrically at the apical cell cortex. More recently, we have found that
the paralog AGS3 (Gpsm1) seems to oppose LGN, and functions in promoting SCDs through an unknown
mechanism. In addition, we recently made the surprising discovery that division orientation is not fixed during
metaphase, as previously thought, but can be further refined during late stages of mitosis. In this process, which
we term “telophase correction,” roughly one-third of basal cells enter anaphase at oblique angles, but then
reorient to either planar or perpendicular. We have learned that cell-cell adhesions—specifically, the
mechanosensing components of the adherens junction—are important for telophase correction to occur, and
can operate independently of LGN. This demonstrates that in addition to intrinsic cues such as the LGN complex,
extrinsic factors such as the local tissue microenvironment influence the final division axis. Despite what we and
others have learned about the molecular control of ACDs, major knowledge gaps exist in understanding how
oriented divisions shape tissue architecture both during normal development and in congenital skin diseases
such as epidermolysis bullosa and ectodermal dysplasia. Specifically, the objectives of this proposal are to
develop a better understanding of 1) what regulates SCDs and how the choice between SCD/ACD is made
(SA1), 2) how cell-cell adhesion, cell-matrix, and local cell density impact division orientation and fate decisions
(SA2). To achieve these goals, we will leverage a combination of innovative approaches, centered on our rapid,
high-throughput technique—lentiviral ultrasound-guided gene inactivation and gene expression (LUGGIGE)—
which we will utilize to generate mouse models of both gene loss and of specific mutations found in human
diseases. Combined with ex vivo imaging of skin explants and in vivo proteomic approaches to characterize the
LGN and AGS3 interactomes using TurboID, these comprehensive studies will provide insights into the cell-
intrinsic and extrinsic cues that determine division orientation, and how they operate during normal epidermal
growth and in blistering and dysplastic skin diseases.
摘要
项目成果
期刊论文数量(0)
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专利数量(0)
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SCOTT E WILLIAMS其他文献
SCOTT E WILLIAMS的其他文献
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{{ truncateString('SCOTT E WILLIAMS', 18)}}的其他基金
Intrinsic and extrinsic spindle orientation mechanisms in mammalian epidermis
哺乳动物表皮的内在和外在纺锤体定向机制
- 批准号:
10210677 - 财政年份:2021
- 资助金额:
$ 33.95万 - 项目类别:
Intrinsic and extrinsic spindle orientation mechanisms in mammalian epidermis
哺乳动物表皮的内在和外在纺锤体定向机制
- 批准号:
10360689 - 财政年份:2021
- 资助金额:
$ 33.95万 - 项目类别:
A6A: GENETIC ANALYSIS: REPETITIVE DNA & HETEROCHROMATIN: KELOIDS & HYPERTENSION
A6A:遗传分析:重复 DNA
- 批准号:
6252532 - 财政年份:1997
- 资助金额:
$ 33.95万 - 项目类别:
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