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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

基本信息

批准号：
10585931
负责人：
SCOTT E WILLIAMS
金额：
$ 33.95万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
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：
https://reporter.nih.gov/project-details/10585931
关键词：
Ablation Adherens Junction Adhesions Adhesives Anaphase Apical Architecture Basal Cell Behavior Bulla Cadherins Carcinoma Cell Density Cell Fate Control Cell division Cell-Cell Adhesion Cell-Matrix Junction Cells Communities Complex Cues Daughter Defect Development Disease Ectodermal Dysplasia Embryo Epidermis Epidermolysis Bullosa Epithelium Equilibrium Focal Adhesions GPSM1 gene GPSM2 gene Gene Expression Gene Silencing Genes Genetic Genetic Models Genetic Techniques Goals Growth Hemidesmosomes Homeostasis Homologous Gene Human Hyperplasia Image Integrins Intrinsic factor Junctional Epidermolysis Bullosa Knowledge Label Learning Malignant Neoplasms Mediating Metaphase Mitosis Modality Modeling Molecular Morphogenesis Mutate Mutation Nature Online Mendelian Inheritance In Man Outcome Pathogenesis Pathologic Pathway interactions Pattern Phenotype Phosphorylation Play Positioning Attribute Process Proliferating Property Proteins Proteomics RNA Interference Resources Role Scaffolding Protein Shapes Signal Pathway Skin Skin Abnormalities Stratification Stratified Epithelium Stratum Basale Structure Syndrome Techniques Time Tissues Variant Vinculin Work afadin alpha catenin cell cortex cleft lip and palate cohort ex vivo imaging exhaustion experimental study flexibility human disease in vivo innovation insight knock-down loss of function mechanotransduction mouse model nectin paralogous gene progenitor protein protein interaction real-time images response self-renewal skin disorder skin organogenesis stem stem cell division stem cells telophase therapy development tissue stress tool treatment strategy ultrasound

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