Spindle Orientation in Skin Development and Homeostasis

摘要 必须严格控制细胞分裂方向，才能产生正常的组织结构和细胞 命运。在皮肤中，定向的细胞分裂促进胚胎表皮的分层和 毛囊的形态发生。在成人中，纺锤形取向可以缓冲表皮免受致癌的侮辱。 和组织过度生长。鉴于这些重要的功能，通过以下方式理解这些机制至关重要 有丝分裂的纺锤体是精确定向的。而纺锤体定向所需的一些蛋白质 ，我们并不完全了解这种分子机制是如何在星体上产生力量的 微管可以精确控制细胞分裂方向。我们的初步研究确定了一部小说 表皮纺锤体取向的调节剂。在这里，我们建议进行研究，以掩盖潜在的 这些蛋白质影响分裂方向的机制。此外，我们将使用新的鼠标模型来 明确纺锤形对毛囊形态发生和成人表皮动态平衡的影响。 总而言之，这些数据将提供对主轴定向的更深层次的机械理解 在表皮、心脏和神经发育以及适应性免疫反应中的基本功能。 此外，这项工作与理解纺锤体方向如何控制头发中的细胞命运有直接关系。 发展，以及当动态平衡被扰乱时，它如何作用于抑制组织过度生长。

Abstract Cell division orientation must be tightly controlled for the generation of normal tissue architecture and cell fates. In the skin, oriented cell divisions promote the stratification of the embryonic epidermis and morphogenesis of hair follicles. In adults, spindle orientation buffers the epidermis against oncogenic insults and tissue overgrowth. Given these important functions, it is paramount to understand the mechanisms by which mitotic spindles are precisely oriented. 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 accurate control of cell division orientation. Our preliminary studies have identified novel regulators of epidermal spindle orientation. Here we propose studies to undercover the underlying mechanisms by which these proteins affect division orientation. Further, we will use novel mouse models to define how spindle orientation contributes to hair follicle morphogenesis and adult epidermal homeostasis. 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 understanding how spindle orientation controls cell fates in hair development, and how it acts to suppress tissue overgrowth when homeostasis is perturbed.