Developmental genetics of tooth number variation in sticklebacks

描述（由申请人提供）：牙齿数量的变化与口面裂有关，这是人类最常见的颅面出生缺陷。因此，了解牙齿数量调节的发育和遗传基础对于理解人类颅面和牙齿出生缺陷以及理解牙齿数量规范的基本过程至关重要。虽然对小鼠和人类的遗传研究已经确定了一些与牙齿发育有关的信号通路，但对调节牙齿数量的发育和遗传机制知之甚少。大多数已知的控制哺乳动物颅面和牙齿发育的遗传途径都是高度保守的，并且也涉及包括鱼类在内的低等脊椎动物的颅面和牙齿发育。自然变异背后的遗传变异可以提供对发育过程有价值的见解，并补充模式生物中诱导突变的更传统的遗传研究。本文提出了三刺棘鱼（Gasterosteus aculeatus）牙齿数量的自然变化作为研究基因如何调节牙齿数量的新模型系统。适应不同饮食的不同棘鱼种群在牙齿数量上表现出巨大的变化，淡水鱼的牙齿数量是海鱼的两倍。不同的形式可以在实验室中交叉，使详细的前向遗传分析能够绘制控制牙齿数量变化的因素。全基因组连锁图谱已经确定了10个染色体区域，或数量性状位点（QTL），控制刺鱼的牙齿数量，并确定了确定潜在基因的方法。为了验证关于牙齿数量差异的发育和分子遗传学基础的假设，提出了三个具体目标。首先，海洋和淡水种群中牙齿差异的发育时间过程将通过分析胚胎、幼虫和幼崽的骨骼分化来确定。其次，通过比较海鱼和淡水鱼颅面和牙齿组织发育过程中的基因表达模式，确定与牙齿数量差异相关的基因表达。第三，通过定位、测序、基因表达和转基因实验，确定棘鱼21号染色体上控制牙齿生长的QTL的遗传基础。

DESCRIPTION (provided by applicant): Changes in tooth number are associated with orofacial clefting, the most common craniofacial birth defect in humans. Thus, knowledge of the developmental and genetic basis of tooth number regulation is critical for understanding human craniofacial and dental birth defects, as well as for understanding the fundamental process of tooth number specification. Although genetic studies in mice and humans have identified several signaling pathways involved in tooth development, little is known about the developmental and genetic mechanisms regulating tooth number. Most genetic pathways known to control mammalian craniofacial and tooth development are highly conserved and are also involved in craniofacial and tooth development in lower vertebrates, including fish. Genetic variants underlying natural variation can provide valuable insight into developmental processes and complement more traditional genetic studies of induced mutations in model organisms. Here natural variation in tooth number in the threespine stickleback fish (Gasterosteus aculeatus) is proposed as a new model system to learn how genes regulate tooth number. Different stickleback populations adapted to different diets exhibit dramatic changes in tooth number, with freshwater fish having twice the number of teeth as marine fish. The different forms can be crossed in the lab, enabling detailed forward genetic analyses to map factors controlling the changes in tooth number. Genome-wide linkage mapping has identified ten chromosome regions, or quantitative trait loci (QTL), controlling tooth number in sticklebacks, and methods are in place to identify the underlying genes. To test hypotheses about the developmental and molecular genetic basis of the tooth number differences, three specific aims are proposed. First, the developmental time course of the tooth differences seen in marine and freshwater populations will be determined by analyzing skeletal differentiation in embryos, larvae, and juveniles. Second, gene expression correlates of the tooth number differences will be identified by comparing gene expression patterns in developing craniofacial and dental tissues from marine and freshwater fish. Third, the genetic basis of a QTL on stickleback chromosome 21 controlling tooth gains will be identified by mapping, sequencing, gene expression, and transgenic experiments.