Establishment of Long-Range Tissue Polarity in the Mammalian Epidermis

描述（由申请人提供）：细胞如何组装成复杂的排列，使组织具有特殊功能是生物学中的一个基本问题。为了组织的正常组装，细胞的自组织特性必须与远程信号相协调，这些信号将组织组织成体内正确的方向或极性。尽管使用遗传模式生物进行了广泛的研究，但这些远程极化信号的身份仍然未知。随着再生医学领域向从多能干细胞中产生任何类型细胞的方向发展，发现成人组织适当三维组织所需的远程信号将是至关重要的。组织极性或平面细胞极性（PCP）是指细胞沿上皮平面全局的集体极化，PCP的遗传破坏可导致神经管缺陷、囊性肾病、听力丧失、纤毛病和心脏缺陷等严重发育障碍。虽然跨物种保守的一组核心PCP基因负责在短距离内细胞间传递方向信号，但在长距离内是什么使极性在全球范围内向特定方向倾斜尚不清楚。一种可能性是，在组织中以浓度梯度表达的分泌或细胞外信号可以提供全局极化提示。另外，极化细胞与其底层基质之间的物理相互作用，或形态发生过程中施加的机械力可能导致细胞极性的全局对齐。确定远距离极化信号的来源将解决极性领域长期存在的难题，并对组织工程领域产生深远的影响。本提案的目标是确定协调远距离组织极性的分子和物理线索，并破译细胞如何不对称地重组以响应这些定向线索。哺乳动物皮肤是自然界中极化最显著的组织之一，研究人员将采用基因组学、蛋白质组学、成像、遗传学和生物物理学方法的结合来：(1)确定渐变方向线索如何影响表皮组织的极性；(2)破译外部力量在建立长程组织极性中的作用；(3)阐明细胞极化响应方向信号的机制。下一步是确定指导组织正确三维组织的指导性线索

DESCRIPTION (provided by applicant): How cells assemble into complex arrangements that enable the specialized function of a tissue is a fundamental question in biology. For proper tissue assembly to occur, self-organization properties of cells must be coordinated with long-range signals that organize a tissue into the correct orientation, or polarity, within the body. Despite extensive research using genetic model organisms, the identity of these long-range polarizing signals remains unknown. As the field of regenerative medicine advances towards generating any cell type from multipotent stem cells, the discovery of long-range signals required for the proper three-dimensional organization of adult tissues will be essential. Tissue polarity or planar cell polarity (PCP) refers to the collective polarization of cells globally alon the epithelial plane, and genetic disruption of PCP results in severe developmental disorders such as neural tube defects, cystic kidney disease, hearing loss, ciliopathies, and heart defects. While a core set of PCP genes conserved across species is responsible for communicating directional signals from cell to cell over short distances, what biases polarity globally toward a particular direction over long distances is unknown. One possibility is that a secreted or extracellular signal expressed in a concentration gradient across a tissue could provide a global polarizing cue. Alternatively, physical interactions between polarizing cells and their underlying substratum, or mechanical forces exerted during morphogenesis could lead to global alignment of cell polarity. Identifying the source of long-range polarizing signals will solve a long-standin problem in the polarity field and profoundly impact the field of tissue engineering. The goal of this proposal is to identify the molecular and physical cues that orchestrate long-range tissue polarity and to decipher how cells asymmetrically reorganize in response to these directional cues. Using mammalian skin, one of the most strikingly polarized tissues in nature, a combination of genomic, proteomic, imaging, genetic, and biophysical approaches will be employed to: (1) Determine how graded directional cues bias tissue polarity in the epidermis; (2) Decipher the role of external forces in establishing long-range tissue polarity; and (3) Elucidate the mechanisms by which cells polarize in response to directional cues. Identifying the instructive cues that direct the proper three-dimensional organization of a tissue is the next step towards engineering functional organs in vitro. Ultimately, identification of the pathways controlling normal tissue development will help to understand how misregulation of these pathways leads to developmental defects and adult proliferative disorders.