MOLECULAR REGULATION OF HAIR FOLLICLE MORPHOGENESIS

毛囊形态发生调控信号分子的识别和表征仍然是皮肤生物学的主要挑战。该结构在正常的皮肤功能和疾病中起着关键作用：它是伤口愈合和对皮肤损伤的其他反应所需的干细胞的来源；它是几种良性和恶性皮肤肿瘤的发源地；它产生毛干和皮脂腺，其功能障碍构成各种皮肤病的基础。与其他器官相似，毛囊通过一系列感应信号在相邻的上皮细胞和间充质细胞原基之间传递，最终形成成体结构。虽然很明显，毛囊的形态发生需要上皮和间质之间持续的对话，但传递的信息的性质仍然不清楚。Sonic hedgehog(Shh)mRNA编码一种分泌的形态原，参与发育过程中的多种模式事件，在毛囊上皮形成毛囊的表皮中有局部表达。因此，Shh的时空表达与其在毛囊形态发生中发挥的作用是一致的，这一概念得到了我们对无法形成正常毛囊的Shh-/-小鼠的分析支持。基于这些发现和最近的证据表明Hedgehog蛋白在不同脊椎动物器官系统的发育中起关键作用，我们假设Shh作为一种上皮来源的诱导信号调节毛囊的形态发生，这一概念得到了我们对Shh-/-小鼠的分析的支持，因为Shh-/-小鼠无法形成正常的毛囊。基于这些发现和最近的证据表明Hedgehog蛋白在不同脊椎动物器官系统的发育中起关键作用，我们假设Shh在胚胎发育和出生后毛发周期中作为一种上皮来源的诱导信号调节毛囊的发育。我们将使用药理学、免疫学和遗传学的方法来验证这一假说，以在体内和体外调节Shh途径，具体目的如下：1)确定毛囊发育和周期所需的Shh信号；2)确定毛囊中响应Shh信号的靶细胞(S)；3)鉴定和表征毛囊中Shh的遗传靶点；以及4)定义和开发皮肤中介导Shh反应的下游信号元件。我们的研究结果将为毛囊形态发生的机制提供新的见解。考虑到不同的器官使用共同的信号分子来驱动它们的发育这一事实，我们的发现可能与理解其他系统中的器官发生有关。考虑到不同的器官使用共同的信号分子来推动它们的发育这一事实，我们的发现可能与理解其他系统中的器官发生有关。此外，由于Shh途径的几个组成部分与多种人类发育障碍和肿瘤，特别是基底细胞癌和髓母细胞瘤有关，拟议的项目将为我们进一步了解涉及皮肤和其他器官的病理过程提供新的知识。

The identification and characterization of signaling molecules regulating hair follicle morphogenesis remains a major challenge in cutaneous biology. The structure plays a critical role in normal skin function and disease: it is a source of stem cells required during wound-healing and other responses to cutaneous damage; a site of origin for several benign as well as malignant skin tumors; and it produces the hair shaft and sebaceous glands whose dysfunction forms the basis of a variety of dermatological disorders. Similar to other organs, the hair follicle develops through a series of inductive signals traveling between adjacent epithelial and mesenchymal cell primordia which ultimately give rise to the adult structure. While it is clear that an on-going dialogue between epithelium and mesenchyme is required for hair follicle morphogenesis, the nature of the messages being transmitted has remained obscure. Expression of Sonic hedgehog (Shh) mRNA, which encodes a secreted morphogen involved in multiple patterning events during development, is detected focally in epidermis that will give rise to hair follicle epithelium. The spatial and temporal expression of Shh are thus consistent with its playing a role in hair follicle morphogenesis, a concept that is supported by our analysis of Shh-/- mice, which fail to form normal hair follicles. Based on these finding and recent evidence demonstrating a pivotal role for Hedgehog proteins in the development of diverse vertebrate organ systems, we hypothesize that Shh functions as an epithelium-derived inductive signal regulating hair follicle morphogenesis, a concept that is supported by our analysis of Shh -/- mice, which fail to form normal hair follicles. Based on these findings and recent evidence demonstrating a pivotal role for Hedgehog proteins in the development of diverse vertebrate organ systems, we hypothesize that Shh functions as an epithelium-derived inductive signal regulating hair follicle development during embryogenesis and post-natal hair cycling. We will test this hypothesis using pharmacologic, immunologic, and genetic approaches to modulate the Shh pathway, both in vivo and in vitro, with the following specific aims: 1) to determine when Shh signaling is required for hair follicle development and cycling; 2) to identify target cell(s) responding to the Shh signal in hair follicles; 3) to identify and characterize the genetic targets of Shh in follicles; and 4) to define and exploit downstream signaling elements mediating the response to Shh in skin. The results of our studies will provide new insight into mechanisms underlying hair follicle morphogenesis. Given the fact that diverse organs use common signaling molecules to drive their development, our findings are likely to be relevant to understanding organogenesis in other systems. Given the fact that diverse organs using common signaling molecules to drive back their development, our findings are likely to be relevant to understanding organogenesis in other systems. In addition, since several components of the Shh pathway have been linked to a variety of human developmental disorders as well as neoplasia, particularly basal cell carcinoma and medulloblastoma, the proposed project will contribute new knowledge to further our understanding of pathological processes involving skin as well as other organs.