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Investigation of pro-inflammatory effects on CDH1/E-cadherin in the neural crest

Grant number: 19/25350-0
Support type:Scholarships abroad - Research Internship - Post-doctor
Effective date (Start): March 01, 2020
Effective date (End): February 28, 2021
Field of knowledge:Biological Sciences - Genetics
Principal Investigator:Maria Rita dos Santos e Passos Bueno
Grantee:Lucas Alvizi Cruz
Supervisor abroad: Roberto Mayor
Home Institution: Instituto de Biociências (IB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Local de pesquisa : University College London (UCL), England  
Associated to the scholarship:17/11430-7 - Interaction of genetic and epigenetic factors in response to inflammation for the predisposition to cleft lip-palate, BP.PD

Abstract

Oral clefts (OC) are a frequent group of craniofacial malformation caused by a combination of genetic and environmental factors, which may impair craniofacial development by affecting the neural crest (NC). More recently, loss-of-function mutations in genes from the cadherin-catenin complex as CDH1 (E-cadherin) and CTNND1 (p120-catenin) have been found segregating in OC families, however with reduced penetrance. On the other hand, environmental factors as maternal infections and inflammation have been also associated to OC. Interestingly, inflammatory activation has been reported to modulate CDH1/E-cadherin levels in cancer cellular models. E-cadherin is also an important molecule for NC progression and more recently its role has been reported for cranial NC migration. Despite some evidences, it has never been demonstrated that CDH1-associated OC are related to NC deficiencies and how pro-inflammatory processes can affect CDH1 in NC and craniofacial development. Our preliminary data indicates that NC cells are sensible to pro-inflammatory signals and respond by diminishing CDH1 levels. Therefore, our hypothesis is that CDH1 is required for cephalic NC migration and that pro-inflammatory activation inhibits CDH1 expression, impairing NC migration and leading to craniofacial defects as OCs. To test our hypothesis, our central aim is to investigate the cellular and molecular effects of pro-inflammatory activation in NC cells during development with focus on CDH1/E-cadherin function, using in vivo and in vitro quantitative analysis of NC migration. To achieve this aim, we propose to use a pro-inflammatory activation system in zebrafish (Danio rerio) and frog (Xenopus laevis) embryos, which are consecrated animal models for in-depth NC analysis. We also propose a xenograft model using human CDH1-deficient cells into zebrafish embryos to corroborate our hypothesis. We believe that the results from this project will have important impacts on the craniofacial development field and to cancer biology.