The Cichlid Dentition Integrates Tooth Number and Tooth Shape

描述(申请人提供)：尽管哺乳动物的研究有很长的传统，但关于牙齿形状差异的遗传和发育基础仍然存在重要的问题。在这里，我提出了一种研究牙齿形状的新方法。我专注于一个进化模型系统，它展示了牙齿模式的巨大多样性。我的长期目标是确定基因和发育计划，这些基因和发育计划整合了东非马拉维湖慈济鱼物种内和物种之间在牙齿形状和牙齿数量上的差异。这项探索性研究的具体目标是：(I)精确定位控制牙齿形状的蝉类基因组区域，以及(Ii)识别导致蝉类牙齿和牙尖数量相关差异的基因表达模式。明确目标1。确定牙齿形状差异的遗传基础。Cichlid第5号染色体上大约3.5厘米的间隔解释了具有二尖齿和三尖齿的Cichlid物种之间种间杂交的大约40%的表型差异。使用与罗非鱼密切相关的指纹袋库，我将使用新的高通量DMA测序技术，生成跨越该区域的最小平铺路径，并以30-50倍的覆盖率对重叠克隆进行测序。明确目标2.确定决定具有不同齿型的叶蝉类物种在齿数、齿间距和尖数上的差异的发育程序。我将使用原位杂交的方法来研究一些候选基因座(Bmp4；Fgf4，8；Pax9；Dlx1，2；Shh；Pitx2；MSx；Barx1；Edar；ectodin)在慈鱼牙齿形状和图案新颖性产生中的作用。实现上述探索性目标将为确定个体间牙齿形状差异所涉及的基因变化提供所需的基础(目标1)，并将解决具有不同牙齿模式的物种的成牙密码(目标2)。了解慈鱼牙齿模式差异的遗传和发育基础将有助于对脊椎动物牙齿发生的总体洞察，并将为小鼠的研究提供重要的比较数据。结果可能确定人类牙病的新治疗靶点，值得在哺乳动物模型中进行进一步测试。

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.