Head Development: Genetic Determinants and Tissue Potency

涉及主要脑部缺陷(无脑儿和相关畸形)和面部结构(耳朵、面部和颈部)的先天性畸形分别为每10000名新生儿中有3.4%和1.4%(澳大利亚国家围产期统计单位1981年至1996年，先天性畸形)，并构成很大的临床负担。人们认为，这些主要的结构缺陷通常是由于怀孕前三个月的异常发育造成的，这与小鼠胚胎头部基本成分的形成时间框架不谋而合。因此，小鼠模型中头部形成的知识与理解人类早期发育的相关发育过程有关。该项目对转基因和遗传操作产生的小鼠胚胎进行了复杂的胚胎学和分子分析，为人类早期发育的哺乳动物模型提供了详细的头面部形态发生研究。显微操作、胚胎培养、荧光显微镜和原位杂交是我们实验室的常规操作程序，大多数小鼠品系都在我的实验室建立得很好。为该项目提出的实验将重点放在对正常和突变胚胎的胚胎学和分子分析上，应该会发现关于调节头部发育的细胞和分子机制的新信息。这一知识也将为其他突变胚胎中类似的颅面畸形的发病机制提供洞察力。

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.