Developmental Gene Expression In C Elegans

我们对在发育过程中调控细胞命运决定的转录因子感兴趣。我们的模型系统是秀丽隐杆线虫（一种非寄生蠕虫），由于其体积小，易于在实验室培养，解剖简单，增殖迅速和遗传学，被广泛用于发育研究。我们目前对在其他系统中发现的对中胚层模式和肌肉形成重要的转录因子感兴趣。通过与华盛顿卡内基研究所Andy Fire博士的团队合作，我们已经证明秀丽隐杆线虫MyoD和Twist转录因子对包括肌肉在内的胚胎后中胚层细胞的形成和模式很重要。通过研究这些基因突变导致的表型，我们开始确定它们在调节秀丽隐杆线虫特定肌肉细胞亚群发育中的确切作用。此外，我们研究的一种突变体，Twist的半显性等位基因，与导致saethree - chotzen综合征的人类Twist突变有有趣的相似之处。这种综合征与颅面和其他发育缺陷有关。我们在秀丽隐杆线虫中的结果表明，某些人类Twist等位基因作为显性负蛋白发挥作用，这是以前没有考虑过的概念。我们的秀丽隐杆线虫突变体也为基因筛选提供了一个起点，以确定在控制中胚层发育的调节层次中运作的其他因素。线虫提供了用单细胞分辨率研究中胚层发育的转录调控的机会，这将使我们对人类发育和疾病的理解做出重要贡献。

We are interested in transcription factors that function in the regulation of cell fate determination during development. Our model system is the nematode C. elegans (a non-parasitic worm) that is widely used for developmental studies because of its small size, ease of culture in the laboratory, simple anatomy, rapid proliferation, and genetics. We are currently interested in several transcription factors that have been identified in other systems as important for mesoderm patterning and muscle formation. In collaboration with Dr. Andy Fire's group at the Carnegie Institution of Washington we have shown that the C. elegans MyoD and Twist transcription factors are important for the formation and patterning of post-embryonic mesodermal cells including muscle. By studying the phenotypes that result from mutations in these genes we are beginning to define their exact roles in regulating the development of specific subsets of muscle cells in C. elegans. In addition, one of the mutants we study, a semi-dominant allele of Twist, has interesting parallels to Twist mutations in humans that result in Saethre-Chotzen syndrome. This syndrome is associated with craniofacial and other developmental defects. Our results in C. elegans suggest that certain human Twist alleles are functioning as dominant negative proteins, a notion not previously considered. Our C. elegans mutants also provide a starting point for genetic screens to identify other factors operating in the regulatory hierarchy controlling mesoderm development. The nematode offers the opportunity to study the transcriptional regulation of mesoderm development with single cell resolution which will allow us to make important contributions to the understanding of human development and disease.