The Cichlid Dentition Integrates Tooth Number and Tooth Shape

描述（由申请人提供）：尽管对哺乳动物的研究有着悠久的传统，但关于牙齿形状差异的遗传和发育基础仍然存在重要问题。在这里，我提出了一种新的方法来研究牙齿形状。我专注于一个进化模型系统，它展示了牙齿图案的巨大多样性。我的长期目标是确定基因和发育程序，整合牙齿形状和牙齿数量的差异，内部和物种之间的慈鲷鱼从马拉维湖，东非。这项探索性研究的具体目标是：(i)绘制控制牙齿形状的慈鲷基因组区域的精细图谱；（ii）确定产生慈鲷牙齿和齿尖数量相关差异的基因表达模式。具体目标确定牙齿形状差异的遗传基础。慈鲷5号染色体上约3.5厘米的间隔解释了两尖牙与三尖牙慈鲷种间杂交中约40%的表型差异。利用密切相关罗非鱼的指纹BAG文库，我将使用新的高通量DMA测序技术，在该区域生成最小平铺路径，并以30-50倍的覆盖率对重叠克隆进行测序。具体目标2。确定发育程序，决定差异的牙齿数量，牙齿间距和尖的数量在不同种类的慈鲷之间的牙齿模式。我将使用原位杂交来研究一些候选基因座（Bmp4、Fgf4、8、Pax9、Dlx1、2、Shh、Pitx2、Msx、Barx1、Edar、ectodin）在幼鱼牙齿形状和图案新异产生中的作用。完成上述探索目标将为识别个体之间牙齿形状差异的遗传变化提供必要的基础（目标1），并将解决具有不同牙齿模式的物种的牙源密码（目标2）。了解鱼鱼牙齿形态差异的遗传和发育基础，将有助于深入了解脊椎动物的牙形成，并为小鼠研究提供重要的比较数据。结果可能为人类牙齿疾病确定新的治疗靶点，值得在哺乳动物模型中进一步测试。

DESCRIPTION (provided by applicant): Despite a long tradition of study in mammals, important questions remain regarding the genetic and developmental basis of differences in tooth shape. Here, I propose a novel approach to the study of tooth shape. I concentrate on an evolutionary model system that exhibits tremendous diversity in dental patterning. My long-term goal is to identify the genes and the developmental programs that integrate differences in tooth shape and tooth number, within and among species of cichlid fish from Lake Malawi, East Africa. The specific goals of this exploratory research are to (i) fine map a region of the cichlid genome that controls tooth shape and (ii) identify patterns of gene expression that generate correlated differences in cichlid tooth and cusp number. Specific Aim 1. Identify the genetic basis of differences in tooth shape. An approximately 3.5 centimorgan interval on cichlid chromosome 5 explains about 40% of the phenotypic variance in an interspecific cross between cichlid species with bicuspid vs. tricuspid teeth. Using fingerprinted BAG libraries in the closely-related tilapia, I will generate a minimum tiling path across this region and sequence overlapping clones at 30-50x coverage, using new high-throughput DMA sequencing technology. Specific Aim 2. Identify the developmental programs that determine differences in tooth number, tooth spacing and cusp number among cichlid species with divergent dental patterns. I will use in situ hybridization to study the role of a number of candidate loci (Bmp4; Fgf4,8; Pax9; Dlx1,2; Shh; Pitx2; Msx; Barx1; Edar; ectodin) in the generation of novelty in cichlid tooth shape and patterning. Accomplishing the exploratory aims outlined above will provide the foundation required to identify genetic changes involved in tooth shape differences among individuals (Aim 1) and will solve the odontogenic code for species with different dental patterning (Aim 2). Knowledge of the genetic and developmental basis of differences in cichlid tooth patterning will lend general insight into vertebrate odontogenesis and will contribute important comparative data for studies in mouse. Results may identify novel therapeutic targets for human dental disorders that warrant further testing in mammalian models.