Developmental genetics of tooth number variation in sticklebacks

描述(申请人提供)：牙齿数量的变化与口面部裂伤有关，口面部裂伤是人类最常见的头面部出生缺陷。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了解牙齿数量指定的基本过程是至关重要的。尽管对小鼠和人类的遗传学研究已经确定了几个与牙齿发育有关的信号通路，但对调控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是高度保守的，也参与了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的有价值的见解，并补充模式生物中诱导突变的更传统的遗传学研究。本文提出了三刺鱼(Gasterbone Us Aculeatus)牙数的自然变异作为研究基因调控牙数的一个新的模式系统。适应不同食物的不同刺鱼种群的牙齿数量发生了戏剧性的变化，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，使详细的正向遗传分析能够绘制出控制牙齿数量变化的因素。全基因组连锁图谱已经确定了控制刺鱼牙齿数量的10个染色体区域或数量性状基因座(QTL)，并且已经有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，将通过分析胚胎、幼虫和幼虫的骨骼分化来确定在海洋和淡水种群中出现的牙齿差异的发育时间进程。其次，通过比较海水鱼和淡水鱼发育中的头面部和牙齿组织中的基因表达模式，将确定牙齿数量差异的基因表达相关性。第三，将通过定位、测序、基因表达和转基因实验来鉴定21号染色体上控制牙齿获得的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.