An epidermal mechanism for digit separation

项目总结/摘要 对鸟类和哺乳动物趾形成的发育生物学研究有着悠久的历史， 数字分离过程的细胞和分子基础。在细胞水平上， 趾间间充质以及差异性趾和趾间生长介导趾分离。的 指间细胞凋亡是通过减少上覆表皮中FGF 8的表达而启动的， 指间间充质中分子变化的级联反应，最终导致细胞凋亡和退化 趾间组织的组织这一过程的失败被认为是许多先天性畸形的基础， 融合手指的人类，这种情况在每10000个新生儿中观察到3-10个。通过我们在Grhl 3-/-上的工作， 在小鼠中，我们发现了一种全新的基于上皮的手指分离机制。我们的数据表明 虽然指间凋亡是指分离所必需的，但这是不够的。我们发现了一种 小的多层上皮舌结构（称为趾间上皮舌; IET）近端， 分开的手指连接处对于正常的手指形成，该结构内的上皮细胞需要经历 分叉伴随趾间间充质细胞死亡。本申请中的假设是：1） 当趾间接合处上皮向近端移动时， 由于趾间充质细胞死亡，在其前端形成多层上皮舌结构。 边缘;和2）GRHL 3控制的途径是指间上皮舌分叉所必需的， 允许数字分隔。我们提出了两个目标来检验这些假设。在目标1中，我们将描述 负责趾间上皮舌运动和分叉的细胞机制。在目标2中， 将定义一个GRHL 3调节的分子通路，负责趾间上皮分叉， 舌头.这些研究具有重要意义和创新性，因为它们定义了一种以前未被认识到的细胞 和正常手指分离所需的分子途径。

PROJECT SUMMARY/ABSTRACT A long history of developmental biology research into avian and mammalian digit formation has defined the cellular and molecular underpinnings of the digit separation process. At a cellular level, apoptosis of the interdigital mesenchyme, as well as differential digit and interdigital growth, mediate digit separation. The interdigital apoptosis is initiated by decreasing FGF8 expression in the overlying epidermis which triggers a cascade of molecular changes in the interdigital mesenchyme, ultimately resulting in apoptosis and regression of the interdigital tissue. A failure of this process is thought to underlie a number of congenital abnormalities in humans with fused digits, a condition observed in 3-10 per 10 thousand births. Through our work on Grhl3-/- mice, we discovered an entirely new epithelial-based mechanism for digit separation. Our data suggest that while interdigital apoptosis is required for digit separation it is not sufficient. We identified the formation of a small multilayered epithelial tongue structure (referred to as the interdigital epithelial tongue; IET) proximally at the separating digit junctions. For normal digit formation, the epithelia within this structure needs to undergo bifurcation concomitant with the interdigital mesenchymal cell death. The hypotheses in this application are: 1) that as the interdigital juncture epithelium moves proximally and from the dorsal and ventral surfaces in response to interdigital mesenchyme cell death, a multilayered epithelial tongue structure forms at its leading edge; and 2) that a GRHL3-controlled pathway is required for bifurcation of the interdigital epithelial tongue to allow digit separation. We propose two Aims to test these hypotheses. In Aim 1, we will characterize the cellular mechanisms responsible for movement and bifurcation of the interdigital epithelial tongue. In Aim 2, we will define a GRHL3-regulated molecular pathway responsible for bifurcation of the interdigital epithelial tongue. These studies are significant and innovative because they define a previously unrecognized cellular and molecular pathway required for normal digit separation.