Head Development: Genetic Determinants and Tissue Potency

先天性畸形涉及脑（无脑和相关异常）和面部结构（耳、脸和颈部）的重大缺陷，每10000名新生儿中分别有3.4人和1.4人患有先天性畸形（澳大利亚先天性畸形，1981-1996年，全国围产期统计单位），它们构成了沉重的临床负担。人们认为，这些主要的结构缺陷通常是由于前三个月的异常发育造成的，这与小鼠胚胎头部基本成分形成的时间框架相吻合。因此，了解小鼠模型中头部的形成与理解早期人类发育的相关发育过程有关。这个项目涉及到对转基因和基因操作产生的小鼠胚胎进行复杂的胚胎学和分子分析的应用，为早期人类发育的哺乳动物模型提供了颅面形态发生的详细研究。显微操作程序，胚胎培养，荧光显微镜和原位杂交在我们实验室常规进行，大多数小鼠系在我的实验室建立得很好。本项目提出的实验重点是正常和突变胚胎的胚胎学和分子分析，将发现有关调节头部发育的细胞和分子机制的新信息。这些知识也将为其他突变胚胎中类似颅面畸形的发病机制提供见解。

Congenital malformations involving major defects of brain (anencephalus and related anomalies) and facial structures (ear, face and neck) are encountered in 3.4 and 1.4 per 10000 births respectively (Congenital Malformations Australia 1981-1996, National Perinatal Statistics Unit) and they constitute a substantial clinical burden. It is believed that these major structural defects usually result from abnormal development in the first trimester, which coincides with the time frame for the formation of the basic components of the embryonic head in the mouse. Knowledge of the formation of the head in the mouse model is therefore relevant to the understanding of related developmental processes in early human development. This project which involves the application of sophisticated embryological and molecular analyses on mouse embryos generated by transgenesis and genetic manipulation provides a detailed studies of craniofacial morphogenesis in a mammalian model for early human development. The micro-manipulation procedures, embryo culture, fluorescence microscopy and the in situ hybridization are routinely performed in our laboratory, and most of the mouse lines are well established in my laboratory. Experiments proposed for this project that focus on the embryological and molecular analysis of normal and mutant embryos should discover new information on the cellular and molecular mechanisms that regulate head development. The knowledge will also offer insight into the pathogenesis of similar craniofacial malformations in other mutant embryos.