Spindle Orientation in Skin Development and Homeostasis

皮肤发育和稳态中的纺锤体方向

• 批准号: 9761985
• 负责人: Terry H Lechler
• 金额: $ 33.78万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9761985
• 关键词: 3-Dimensional; Adaptor Signaling Protein; Address; Adult; Alopecia; Architecture; Binding; Biology; Cardiac development; Cell Differentiation process; Cell division; Cells; Complex; Data; Defect; Development; Disease; Embryo; Environment; Epidermis; Family member; Foundations; Functional disorder; Generations; Genetic; Genetic Models; Goals; Growth; Hair; Hair follicle structure; Homeostasis; Image; In Vitro; Invertebrates; Kinesin; Knowledge; Long-Term Effects; Mammals; Microtubule Depolymerization; Microtubules; Mitotic spindle; Molecular; Morphogenesis; Morphology; Mus; Neonatal; Normal tissue morphology; Organ; Physiological; Plant Roots; Premature Infant; Proliferating; Proteins; Randomized; Reagent; Role; Skin; Skin Cancer; Stratification; Structure; Testing; Tissues; Tumor Suppressor Genes; Work; adaptive immune response; appendage; base; cell type; clinical development; depolymerization; hair follicle disorder; in vitro Assay; keratinocyte; mature animal; mouse model; mutant; mutant mouse model; neurodevelopment; novel; prevent; public health relevance; response; skin organogenesis; tool; tumor; tumor growth; tumorigenesis

 DESCRIPTION (provided by applicant): Cell division orientation must be tightly controlled for the generation of normal tissue architecture. In the skin, asymmetric cell divisions that are driven by oriented mitotic spindles promote both the stratification and differentiation of the embryonic epidermis. While some of the proteins required for spindle orientation have been identified, we do not fully understand how this molecular machinery generates forces on astral microtubules to allow precise control of cell division orientation. In addition, the essential requirement of spindle orientation in embryonic epidermal development has prevented analysis of the function of these divisions in adult skin. Roles for spindle orientation in the morphogenesis of hair follicles, which are highly organized epidermal appendages, have not been addressed. Similarly, whether spindle orientation is required for homeostasis of the adult interfollicular epidermis has not been tested. This is despite long- standing hypotheses that loss of spindle orientation could promote tumorigenesis. Our preliminary studies have identified an unexpected mechanism required for spindle orientation in keratinocytes which we will elucidate in detail in Aim 1. These mechanistic studies allowed us to generate a mutant mouse model in which spindle orientation was randomized in the epidermis, resulting in neonatal lethality. Importantly, disruption of spindle orientation in adult animals caused both severe hair follicle defects and interfollicular hyperproliferation and local invasion. We will use this new genetic model to determine the specific roles for spindle orientation in hair follicle morphogenesis (Aim 2) and adult interfollicular epidermal homeostasis and tumorigenesis (Aim 3). Together, these data will provide a deeper mechanistic understanding of spindle orientation which has essential functions in epidermal, cardiac and neural development as well as the adaptive immune response. In addition this work has direct relevance for both understanding and eventually treating alopecias/hair follicle disorders and skin cancer.

 描述（由申请人提供）：必须严格控制细胞分裂方向以生成正常组织结构。在皮肤中，由定向有丝分裂纺锤体驱动的不对称细胞分裂促进胚胎表皮的分层和分化。虽然已经确定了纺锤体方向所需的一些蛋白质，但我们并不完全了解这种分子机制如何在星形微管上产生力，以精确控制细胞分裂方向。此外，胚胎表皮发育中纺锤体取向的基本要求阻碍了对成人皮肤中这些部门功能的分析。毛囊是高度组织化的表皮附属物，纺锤体取向在毛囊形态发生中的作用尚未得到解决。同样，纺锤体取向是否需要成年毛囊间表皮的稳态尚未测试。这与长期存在的纺锤体方向丢失可能促进肿瘤发生的假设无关。我们的初步研究已经确定了一个意想不到的机制所需的角化细胞，我们将详细阐明的目的1。这些机制研究使我们能够产生突变小鼠模型，其中表皮中纺锤体方向随机化，导致新生儿死亡。重要的是，在成年动物中，纺锤体方向的破坏导致严重的毛囊缺陷和毛囊间过度增殖和局部浸润。我们将使用这个新的遗传模型来确定毛囊形态发生（目标2）和成人毛囊间表皮稳态和肿瘤发生（目标3）中纺锤体方向的具体作用。总之，这些数据将提供一个更深层次的机械理解的纺锤体方向，在表皮，心脏和神经发育以及适应性免疫反应的基本功能。此外，这项工作与理解和最终治疗脱发/毛囊疾病和皮肤癌有直接关系。