Genetic studies of a pleiotropic transmembrane protease: insight from color variation in non-model organisms

项目摘要/摘要 孟德尔色泽变异是鉴定和研究相关信号通路的丰富遗传资源 对人类生物学有影响，但影响小鼠和人类毛色的突变全套 变得饱和。基因组测序技术的进步现在扩展了正向遗传学的范围 从人类和模式生物到家养和野生动物，其中有许多色素 表型可能代表保守的信号通路，但其分子基础尚不清楚。 利用家猫的色素变异，我们的研究小组发现了一种惊人的联系 跨膜型氨基肽酶Q(Taqpep)编码的新型跨膜蛋白酶及其分泌型Wnt 由Dickkopf 4(Dkk4)编码的抑制物。Taqpep基因敲除小鼠的初步研究揭示了在多个细胞中的作用 类型和组织，包括头发、肠道神经系统和上颚。在不同的非模型生物体中， 在卢旺达与世隔绝的种群中，平原斑马Taqpep是异常条纹的候选基因。 我们的结果指出了Taqpep在与人类直接相关的途径和组织中的中心作用 生物学和疾病，但对这些途径的分子理解最有效的方法是 将正向遗传学用于非模式哺乳动物生物的基因发现与实验遗传学相结合 在实验室小鼠和培养的哺乳动物细胞中进行研究。我们建议： (1)通过孟加拉猫的正向遗传学和对胎儿的分析，确定Taqpep作用的其他成分 猫皮 (2)扩大斑马颜色模式变异的初步遗传研究 (3)用实验小鼠遗传学和蛋白质组学方法确定Taqpep的作用机制

Project Summary/Abstract Mendelian variation in pigmentation is a rich genetic resource to identify and study signaling pathways relevant to human biology, but the repertoire of mutations that affect pigmentation in mice and in humans coat color has become saturated. Advances in genome sequencing technology now extend the reach of forward genetics beyond humans and model organisms to domestic and wild animals, for which there are many pigmentary phenotypes likely to represent conserved signaling pathways but whose molecular basis is unknown. Using pigmentary variation in domestic cats, our research group discovered a striking connection between a novel transmembrane protease encoded by Transmembrane aminopeptidase Q (Taqpep) and a secreted Wnt inhibitor encoded by Dickkopf 4 (Dkk4). Initial studies of Taqpep knockout mice reveal a role in multiple cell types and tissues including hair, the enteric nervous system, and the palate. In a different non-model organism, the plains zebra, Taqpep is a candidate gene for aberrant striping in an isolated population in Rwanda. Our results point to a central role for Taqpep in pathways and tissues that are directly relevant to human biology and disease, but a molecular understanding of those pathways is most effectively approached by combining forward genetics for gene discovery in non-model mammalian organisms with experimental genetics in laboratory mice and studies in cultured mammalian cells. We propose to: (1) Identify additional components of Taqpep action by forward genetics in Bengal cats and by analysis of fetal cat skin (2) Expand initial genetic studies of color pattern variation in zebras (3) Determine the mechanism of Taqpep action using experimental mouse genetics and proteomics