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In vitro characterization of the redox state and TCOF1 expression during human craniofacial development

Grant number: 20/08189-9
Support Opportunities:Scholarships in Brazil - Scientific Initiation
Effective date (Start): November 01, 2020
Effective date (End): October 31, 2021
Field of knowledge:Biological Sciences - Genetics - Human and Medical Genetics
Principal Investigator:Maria Rita dos Santos e Passos Bueno
Grantee:Diogo Andrade Nani
Host Institution: Instituto de Biociências (IB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated research grant:13/08028-1 - CEGH-CEL - Human Genome and Stem Cell Research Center, AP.CEPID


The craniofacial system development begins in the embryo with the neuroectodermal specification. This process leads to the emergence of neuroectodermal territories: the neural plate and neural plate border, which are, respectively, specified by intermediate and low levels of BMP pathway activation. It is known that the BMP pathway and the production and signalling of reactive oxygen species (ROS) are reciprocally influenced, and also that ROS can cause oxidative damage to the DNA. Cranial neural crest cells originate from the neural plate border, being responsible for the craniofacial complex formation. Thus, apoptosis due to oxidative stress and DNA damage in the neural plate border cells may result in craniofacial abnormalities, such as the Treacher Collins Syndrome (TCS). Most of TCS' cases are caused by mutations in gene TCOF1, which encodes a protein (treacle) important for the process of DNA oxidative damages repairment. TCS' phenotype exclusively affects the formation of craniofacial bones and cartilage structures derived from the neural plate border/cranial neural crest, being the ones derived from the neural plate less or not affected. Thus, our hypothesis predicts that the neural plate border presents a higher production of ROS and, therefore, requires a higher demand of the oxidative DNA damage repair machinery during its differentiation, compared to the neural plate. To test our hypothesis, we will use induced pluripotent stem cells (iPSC) derived from clinically normal subjects differentiated into neural plate and neural plate cells. We will also evaluate whether the activation of BMP pathway, the redox state and the TCOF1/treacle expression levels differ between these two cell types. This study will contribute to increase the knowledge of processes that occur during the human craniofacial development, as well as to elucidate the molecular causative mechanisms of the TCS and other craniofacial syndromes.

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