Role of inflammation on craniofacial morphogenesis

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.

Cephalic neural crest is a highly migratory embryonic cell population that colonizes and originates most of the face of humans and other vertebrates. Therefore, any problem in their migration can have devastating consequences, leading to craniofacial malformations. Some of the most common craniofacial malformations are oral clefts, such as lip and palate clefts.

Epidemiological and genetic evidence lead us to propose the idea that oral clefts are generated by an inflammatory response triggered in the cephalic neural crest. It has been shown that inflammation in gastric cancers leads to down regulation of E-cadherin by triggering hypermethylation of its promoter. This evidence together with our preliminary data allow us to propose the hypothesis that a pro-inflammatory response in the neural crest impairs its migration by inhibiting E-cadherin expression.

To test this hypothesis, we will answer the following questions:

1a. Does inflammation inhibit cephalic neural crest migration?
1b. What is the cellular behaviour affected by inflammation during neural crest migration?
2a. Is E-cadherin required in the neural crest for its migration?
2b. Which cell behaviour is controlled by E-cadherin during neural crest migration?
3a. What is the molecular mechanism by which inflammation inhibits E-cadherin expression during neural crest migration?
3b. Is an intrinsic basal pro-inflammatory response required for normal neural crest migration?

This project will demonstrate for the first time the role of inflammation and E-cadherin on cephalic neural crest migration and will identify the mechanism by which inflammation controls E-cadherin expression. The results of this project will have a high impact in understanding and generating new diagnostics and preventive strategies for oral cleft malformations.