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，口面裂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。虽然在小鼠和人类的遗传研究已经确定了几个参与牙齿发育的信号通路，但对调节牙齿数量的发育和遗传机制知之甚少。已知控制哺乳动物颅面和牙齿发育的大多数遗传途径是高度保守的，并且也参与包括鱼类在内的低等脊椎动物的颅面和牙齿发育。作为自然变异基础的遗传变异可以为发育过程提供有价值的见解，并补充模式生物中诱导突变的传统遗传学研究。在这里，自然变化的牙齿数量在threespine棘鱼（Gasterosteus aculeatus）提出了一个新的模型系统，以了解基因如何调节牙齿数量。不同的棘鱼种群适应不同的饮食表现出巨大的牙齿数量变化，淡水鱼的牙齿数量是海水鱼的两倍。不同的形式可以在实验室中交叉，从而进行详细的遗传分析，以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，或数量性状基因座（QTL），控制棘鱼的牙齿数量，方法是适当的，以确定潜在的基因。为了验证牙齿数量差异的发育和分子遗传基础的假设，提出了三个具体目标。首先，在海洋和淡水种群中看到的牙齿差异的发育时间过程将通过分析胚胎，幼虫和青少年的骨骼分化来确定。其次，将通过比较海水鱼和淡水鱼的颅面和牙齿组织发育中的基因表达模式来确定牙齿数量差异的基因表达相关性。第三，将通过作图、测序、基因表达和转基因实验来确定棘鱼21号染色体上控制牙齿增加的QTL的遗传基础。 公共卫生相关性：这项研究将提供基因如何控制牙齿数量的基础知识。这些知识将有助于体外牙齿形成工程的努力。此外，由于牙齿数量的变化与常见的人类颅面出生缺陷有关，因此这些知识将有助于更好地了解和预防人类颅面和牙齿出生缺陷。

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. PUBLIC HEALTH RELEVANCE: This research will provide fundamental knowledge of how genes control tooth number. This knowledge will help efforts to engineer tooth formation in vitro. In addition, since changes in tooth number are associated with common human craniofacial birth defects, this knowledge will lead to a better understanding and prevention of human craniofacial and dental birth defects.