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:10360689
- 负责人:
- 金额:$ 30.55万
- 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 BullosaEpithelialEquilibriumFocal AdhesionsGPSM1 geneGPSM2 geneGene ExpressionGene SilencingGenesGeneticGenetic ModelsGenetic TechniquesGoalsGrowthHomeostasisHomologous GeneHumanHyperplasiaImageIntegrinsIntrinsic factorJunctional Epidermolysis BullosaKnowledgeLabelLeadMalignant NeoplasmsMediatingMetaphaseMitosisModelingMolecularMorphogenesisMutateMutationNatureOnline Mendelian Inheritance In ManOutcomePathogenesisPathologicPathway interactionsPatternPhenotypePhosphorylationPlayPositioning AttributeProcessPropertyProteinsProteomicsRNA 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.
抽象的
正确控制干细胞分裂对于组织形态发生和稳态至关重要。
可以导致发育不全和干细胞疲惫一只手
但是有丝分裂不仅仅是简单的增殖,因为可以控制细胞分裂,而不是在太空中不受欢迎。
定向细胞分裂(OCD)是后者的一个例子,对于茎和祖细胞,选择
分裂轴可以决定细胞命运结果并影响组织结构。
表皮,基底祖细胞在上皮的平面内划分或垂直
表明平面分裂通常是自我更新的对称细胞划分(SCD),而垂直于
分裂是区分不对称的细胞分裂(ACD)。
由极性和主轴取向蛋白的复合物指导 - 在临界脚手架上
蛋白质LGN(GPSM2) - 最近在根尖细胞皮层中定位。
Paratorog AGS3(GPSM1)似乎反对LGN,并通过未知来促进SCD
机构。此外,我们最近做出了令人惊讶的发现
中期,如前所述,但可以在有丝分裂的后期进一步完善。
我们称“末期校正”,大约三分之一的基层以倾斜角度进入浅色,但是,但是
对平面或垂直的重新定位。
粘附连接的机械症成分 - 对于发生末期的校正很重要,并且
可以独立于LGN运行。
局部组织微环境等外部因素仍会影响最终分裂轴。
其他人了解了ACD的分子控制,在理解如何
定向分裂在发育和先天性皮肤疾病期间塑造组织组织结构
例如表皮溶液和外胚层发育不良。
更好地了解1)SCD的规范以及如何做出SCD/ACD之间的选择
(SA1),2)细胞 - 细胞粘附,细胞 - 矩阵和局部细胞密度影响分裂方向以及命运决定
(SA2)。为了实现目标,我们将利用创新方法的组合
高通量技术静脉内超声引导的基因失活和基因表达(Lugginge) -
我们将利用它来生成基因丧失和人类特异性突变性突变的小鼠模型
疾病与皮肤外植体的体内成像和体内蛋白质组学方法相结合
LGN和AGS3使用涡轮增压体相互作用,这些全面的研究将为细胞提供见解。
确定分裂方向的内在和外在提示,以及在正常表皮期间的运作方式
生长,发脾气和发育不良的皮肤疾病。
项目成果
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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:
10585931 - 财政年份:2021
- 资助金额:
$ 30.55万 - 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:
10210677 - 财政年份:2021
- 资助金额:
$ 30.55万 - 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:
$ 30.55万 - 项目类别:
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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
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10585931 - 财政年份:2021
- 资助金额:
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