FUNCTIONAL ANALYSIS OF GENES INVOLVED IN VERTEBRATE CRANIOFACIAL DEVELOPMENT

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About 75% of birth defects involve the head, face, and oral tissues. Although orofacial clefts and other craniofacial malformations have clear environmental and genetic causes, insufficient information exists concerning the mechanisms of craniofacial development to enable the majority of these defects to be detected or prevented pre-natally. Our goal is to develop animal models of craniofacial malformations that will lead to mechanistic insight into the diagnosis and treatment of related human birth defects. We have recently identified a large set of novel genes that are expressed during the critical stages of mouse face formation. Considerable data has accumulated over the past 25 years that orthologous genes in diverse species often share conserved functions in similar developmental processes. With these observations in mind, we intend to test our hypothesis that genes which are differentially expressed in the mouse craniofacial prominences, and which are conserved in structure and expression in the zebrafish, perform important conserved functions in the development of the vertebrate face that will be relevant to human craniofacial birth defects, including orofacial clefting and micrognathia. The zebrafish provides a very amenable system to rapidly and efficiently screen the functional importance of multiple gene candidates. Zebrafish development occurs externally and can be examined continuously under a microscope. Moreover, gene expression in the zebrafish embryo can be efficiently and easily targeted with specific anti-sense reagents, termed Morpholinos. We will perform two interrelated to Specific Aims. Aim 1. Isolation of zebrafish cDNAs corresponding to the novel and specific orofacial transcripts identified in the embryonic mouse and analysis of their expression profiles during development. Aim 2. MO based knockdown screen in zebrafish to analyze gene function in craniofacial development. Ultimately the results of this study will provide new candidates for an analysis of the underlying causes of related human birth defects. Birth defects affect ~ 3% of all infants born in the US, with about 75% of birth defects involve the head, face, and oral tissues, and the presence of a major birth defect in a newborn will frequently reduce the quality of life for both the child and the parents. Insufficient information exists concerning the mechanisms of craniofacial development to enable the majority of these defects to be detected or prevented pre-natally. We are using animal model systems to determine how normal and abnormal craniofacial development proceeds and to identify new genes that mediate face formation so that we may apply this knowledge to understand and ultimately treat the origins of human facial birth defects.