Role of inflammation on craniofacial morphogenesis

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Oral clefts, such as cleft lip and/or palate, are the most common congenital craniofacial malformation worldwide, and they have devastating effects on children and their families. Genetic studies have indicated that downregulation of the cell adhesion molecule E-cadherin is linked to some oral cleft families, while epidemiological studies have associated maternal infections and maternal fevers to oral clefting in the offspring. Interestingly, evidence suggest that downregulation of E-cadherin is induced by inflammation in cancer gastric. Together, these observations lead us to propose the idea that pro-inflammatory factors activated during embryo development result in inhibition of E-cadherin which is required for normal craniofacial development.Normal craniofacial development depends mainly on the development of cephalic neural crest cells which is an embryonic cell population that migrates from the back to the front of head. Oral clefts have been associated with problems in cephalic neural crest migration. Circumstantial evidence suggests that E-cadherin is required for normal neural crest migration, but this has never been directly tested. Our preliminary experiments in amphibian embryo, an animal model ideally suited for neural crest migration studies, show that induction of inflammation leads to down regulation of E-cadherin and impairment of neural crest migration.In this project we will analyse neural crest migration and E-cadherin levels after inducing a pro-inflammatory response. Our aim is to identify the cellular and molecular mechanism by which inflammation controls neural crest migration. The results of this project will have wide implication in human health as they will contribute to understand the generation of oral cleft malformations, opening new avenues for diagnostic and therapies in the future.