The impact of the FOXG1 gene during human neurodevelopment

• Grant number: 20/02588-9
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• Effective date (Start): January 10, 2022
• Effective date (End): December 24, 2022
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: João Bosco Pesquero
• Grantee: Lauro Thiago Turaça
• Supervisor: Alysson Renato Muotri
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Research place: University of California, San Diego (UC San Diego), United States
• Associated to the scholarship: 19/13637-3 - Pharmacological analyzes in iPSC-derived cardiomyocytes of patients with Fabry Disease, BP.PD

Abstract

Autistic spectrum disorder (ASD) is a complex neurodevelopmental disorder in which different combinations of genetic mutations can contribute to the phenotype. In view of the extensive genetic heterogeneity and the lack of human cell models, it is still a great challenge to clarify the complexity of these disorders. However, the use of reprogrammed somatic cells from patients (induced pluripotent stem cells - iPSCs), to obtain human neurons, has brought a new perspective on the understanding of ASD. Recently, through this technology, we verified in a cohort of 8 patients with macroencephaly, an overexpression of the FOXG1 transcription factor, which is responsible for the overproduction of GABAergic neurons. In addition, the altered expression of the modules of the gene network and FOXG1 is positively correlated with the severity of symptoms. In this work, we propose to generate iPSC organoids in order to obtain neural progenitor cells and neurons from individuals with ASD, carrying some types of molecular changes in the FOXG1 gene. For this, cells from patients with ASD, presenting macroencephaly, in addition to cells edited using the CRISP / CAS9 technique, will be used. With the cultivation of three-dimensional neural cells, the role of the FOXG1 gene in functional organoids of the human brain will be verified, and a possible genotype-phenotype correlation. Finally, the brain organoid model developed is expected to become a valuable tool for therapeutic testing, from drug screening to strategies mediated by viral vectors, such as gene therapy or genome editing. (AU)