A novel low-density lipoprotein receptor-related protein protects against environmental teratogens




Kuka, Timothy Paul

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Congenital malformations are the leading cause of infant mortality in the United States, and 2% of all live births have some form of malformation. While many of these malformations have known genetic or environmental causes, others have eluded explanation. These conditions are thought to be caused by complex interaction between genetic and environmental factors. Prenatal ethanol exposure results in the highest number of preventable birth defects in the United States. Prenatal ethanol exposure interacts with another well-established teratogen: prenatal hyperthermia. Additionally, each of these teratogens interacts with the genetics of the exposed individual. A foreword genetic screen identified a mutation in an uncharacterized locus that sensitizes developing zebrafish to both prenatal ethanol exposure and increased developmental temperature. I identified this locus as a member of the low-density lipoprotein receptor-related protein (LRP) family, and designated it lrp13b. I have found that ethanol teratogenesis in lrp13b mutants is made more severe by increased developmental temperature. Mutants in lrp13b experienced increased apoptosis and fail to properly differentiate facial cartilages when exposed to environmental teratogens. My data suggest that the protective role of lrp13b during development is due to interaction with the fibroblast growth factor (FGF) signaling pathway in the post migratory cranial neural crest. Collectively, these data characterize a novel genetic locus and provide insight into the complex multifactorial etiology of congenital malformations.


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