The identification of genes involved in mammalian craniofacial development and disease

胚胎发育异常引起的出生缺陷是导致婴儿死亡和儿童残疾的主要原因。平均3%-4%的活产婴儿患有严重的先天性异常，在自然流产的15%-20%的怀孕中，许多是由于染色体或其他发育异常。许多发育障碍的一个共同特征是脸部形态异常，这表明在脸部图案形成中重要的基因在其他器官系统的发育中也很重要。在胚胎发育过程中，面部的许多特征来自一系列称为咽弓的肿胀。决定脸部发育的复杂过程在很大程度上是由五对咽弓中的前两对中大量基因的协同表达控制的。虽然我们知道一些参与这些过程的基因，但对颅面发育的确切机制了解相对较少。在这个项目中，我们提出了一种大规模的方法来识别与哺乳动物面部发育有关的基因，并进一步描述它们在发育和人类疾病中的作用。这一方法利用了IMB提供的最先进的基因组技术，并通过现有的海外合作。在与爱荷华大学本托·苏亚雷斯博士的合作下，我们构建了一个文库，其中包含了在发育中的小鼠胚胎的前两对咽弓中表达的所有基因。使用一种旨在消除所有那些在身体所有或大多数组织中表达并在身体新陈代谢中发挥一般作用的基因的方法，我们将选择在胚胎发育中发挥特殊和重要作用的基因。然后，我们将分离这些基因的人类对应基因，并更彻底地研究它们在胚胎发育和疾病中的作用。

Birth defects arising from abnormal development of the embryo are a major cause of infant mortality and childhood disabilities. On average 3-4% of liveborn babies have a major congenital abnormality, and of the 15-20% of pregnancies which spontaneously abort, many are due to chromosomal or other developmental anomalies. A common feature of many developmental disorders is dysmorphology of the face, suggesting that genes important in patterning the face are also important in the development of other organ systems. During development of the embryo many of the features of the face derive from a series of swellings termed the pharyngeal arches. The complex processes which determine how the face develops are in a large part controlled by the co-ordinated expression of a large number of genes in the first two of the five pharyngeal arch pairs. While we know some of the genes involved in these processes, the precise mechanisms of craniofacial development are relatively poorly understood. In this project we propose a large scale approach to identifying genes involved in development of the mammalian face and to further delineating their role in development and human disease. This approach takes advantage of state of the art genomic technologies available at the IMB and through existing collaborations overseas. In collaboration with Dr Bento Soares (University of Iowa) we have constructed a library containing all of the genes which are expressed in the first two pairs of pharyngeal arches in the developing mouse embryo. Using an approach designed to eliminate all those genes which are expressed in all or most tissues of the body and play a general role in the body's metabolism, we will select for those genes which play a specific and important role in embryonic development. We will then isolate the human counterparts of these genes and more thoroughly investigate their role in embryonic development and disease.