Neural tube and orofacial defects are common congenital malformations in humans. Craniofacial birth defects strike an average of 1 in 750 newborns and they are for the most part multifactorial in their pathogenesis, having both genetic and environmental components in their development. Neural Crest cells (NCCs) are a pluripotent cell population that originate in the dorsal neurectoderm to form the facial skeleton and most of the skull. Proper migration of NCCs from the neurectoderm is essential for correct patterning of the craniofacial structures. This migration is dependent on numerous cell signaling pathways which are vulnerable to environmental insults as well as inherited genetic defects. Understanding the temporal and spatial requirements of distinct signaling networks will allow for the development of therapies for specific craniofacial defects. Our approach uses the zebrafish which is amenable to numerous genetic manipulations and is genetically similar to higher mammalian species. In this study we will use a novel craniofacial mutant generated in a large scale ENU mutagenesis screen designed to identify craniofacial mutants. This mutant has neural tube defects and lacks all craniofacial cartilages, a novel defect not isolated in previous ENU screens performed in zebrafish. This work will focus on the molecular and physical characterization of this ghost (gho) mutant and will identify the genetic locus mutated in the gho mutant. These studies will help fill a gap that exists in regards to the identity and timing of the molecular signals required for neural tube closure and the signals required by neural crest cells to adopt specific fates. Our efforts, in addition to the work done in other labs, will ultimately allow for the development of therapeutics for specific early neural tube and craniofacial defects.
Neural tube and orofacial defects are common congenital malformations in humans, striking an average of 1 in 750 newborns. These defects can be caused by environmental teratogens and/or genetic defects. Using a zebrafish mutant that has severe craniofacial defects we will analyze its defective gene, work that will ultimately contribute to understanding part of the network of growth signals required for proper formation of the face, and help scientists develop pre-natal therapies to prevent such malformations.
