Determining the genetic and developmental basis of epidermal appendage evolution

描述(申请人提供)：表皮附属物的发育，如哺乳动物的毛发和鸟类的羽毛和鳞片，为研究与医学相关的过程提供了一个特别容易处理的模型，如命运决定、上皮-间充质相互作用、干细胞维持和血统承诺。在成年生物体中，附件动态平衡的失调可能会导致癌症等疾病，这突显了了解发育是如何控制的重要性。此外，这些附肢还具有重要的健身功能，如调节体温、保护身体免受伤害，对于鸟类来说，还具有运动和视觉交流等功能。虽然毛发和羽毛是哺乳动物和鸟类的定义特征，但这些结构的位置和形态在不同的生物体中差别很大。虽然研究已经确定了一些调节这些附肢形成的遗传机制，但人们对允许它们进化的遗传和发育机制知之甚少。选择性育种在近缘的家鸽品种中产生了巨大的表型多样性。这种多样性，再加上它们胚胎在实验中的可及性，使鸽子成为整合进化和发育遗传学的强大模型。在多种品种中出现的一个有趣的特征是头冠的形成，即头部后部的羽毛具有相反的极性，并向前生长而不是向后生长。此外，尽管许多鸽子品种的脚上都有鳞片，但在一些品种中，鳞片已经被羽毛取代。这项拟议的研究将利用拥有这些特征的国内鸽子品种来了解调节表皮附属物极性和命运的遗传和发育机制，目的有三个。首先，将通过遗传和生化研究来分析与牙冠形成相关的一个强有力的候选基因，以了解它在决定附属器极性方面的作用。其次，通过群体基因组分析和数量性状基因座定位的组合，与决定羽毛与鳞片命运相关的候选基因组区域将被缩小。第三，组织重组实验将用于确定脚部羽化进化过程中信号相互作用的变化，并将通过对鸽子胚胎的遗传操作来测试Aim 2中确定的候选基因，以研究它们在决定表皮器官命运中的作用。这项工作将整合多个层次的研究，以深入了解表皮器官的命运和极性是如何决定的，以及这些特征在进化过程中是如何改变的。这项工作还将开创家鸽作为脊椎动物进化和发育的强大新模式的发展，并将对人类表皮发育和疾病的基础产生深刻的见解。

DESCRIPTION (provided by applicant): The development of epidermal appendages, such as hair in mammals and feathers and scales in birds, provides a particularly tractable model for studying medically-relevant processes such as fate determination, epithelial-mesenchymal interactions, stem cell maintenance, and lineage commitment. In adult organisms, disregulation of appendage homeostasis can lead to diseases such as cancer, highlighting the importance of understanding how development is controlled. In addition, these appendages have important fitness functions such as thermoregulation, protection from physical damage, and in the case of birds, locomotion and visual communication. Although hair and feathers are defining features of mammals and birds, the placement and morphology of these structures varies widely from organism to organism. While research has identified some of the genetic mechanisms regulating formation of these appendages, little is known about the genetic and developmental mechanisms that allow their evolution. Selective breeding has produced tremendous phenotypic diversity among closely-related domestic pigeon breeds. This diversity, coupled with the experimental accessibility of their embryos, makes pigeons an powerful model for integrating evolutionary and developmental genetics. One interesting trait present in multiple breeds is the formation of head crests, whereby feathers on the back of the head have a reversed polarity, and grow forwards instead of backwards. In addition, while many pigeon breeds have scales on their feet, in a number of breeds, scales have been replaced by feathers. The proposed research will utilize domestic pigeon breeds that possess these traits to understand the genetic and developmental mechanisms that regulate epidermal appendage polarity and fate, with three aims. First, a strong candidate gene associated with crest formation will be analyzed through genetic and biochemical studies to understand its role in determining appendage polarity. Second, a candidate genomic region associated with the determination of feather vs. scale fate will be narrowed through a combination of population genomics analyses and quantitative trait locus mapping. Third, tissue recombination experiments will be used to identify how signaling interactions have changed during the evolution of foot feathering, and candidate genes identified in Aim 2 will be tested through genetic manipulation of pigeon embryos to study their role in determining epidermal organ fate. This work will integrate multiple levels of research to generate insight into how epidermal organ fate and polarity are determined, and how these traits are altered during evolution. This work also will pioneer development of the domestic pigeon as a powerful new model of vertebrate evolution and development, and will generate insights into the basis of epidermal development and disease in humans.