Investigation of alterations in neuronal migration in an autism spectrum disorder using human cellular models and animal models

• Grant number: 22/12762-1
• Support Opportunities: Research Projects - Thematic Grants
• Start date: September 01, 2024
• End date: August 31, 2029
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Fabio Papes
• Grantee: Fabio Papes
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• City of the host institution: Campinas
• Associated researchers: Alexandre Bruni Cardoso ; Alysson Renato Muotri ; Andréa Laurato Sertié ; Ângela Saito ; Antônio Pedro de Castello Branco da Rocha Camargo ; Claudio Chrysostomo Werneck ; Deborah Schechtman ; Guilherme Oliveira Barbosa ; Hernandes Faustino de Carvalho ; Lucas Miguel de Carvalho ; Maria Rita dos Santos e Passos Bueno ; Marimélia Aparecida Porcionatto
• Associated scholarship(s): 24/18719-6 - Investigating the role of Ephrin receptors in the neuronal migration process in a monogenic autism spectrum disorder, BP.MS; 25/09026-0 - Study of alterations in neuronal migration in an autism spectrum disorder using brain assembloids, BP.PD; 24/20077-2 - Investigation of the role of Netrin receptors in the cortical disorganization in a monogenic type of autism using cellular models, BP.MS; 24/18734-5 - Study of changes in neuronal migration using autism patient-derived cellular models and microscopy assays, BP.IC; 24/12825-9 - Manipulation of TCF4 gene expression to assess its necessity in neuronal migration using in vitro cellular models., BP.IC

Abstract

Autism spectrum disorders comprise a group of neuropsychiatric diseases caused by problems during neurodevelopment. They are characterized by altered social behavior, impaired communication, and repetitive behaviors. Since the genetic, molecular, and cellular mechanisms of these disorders have not yet been fully elucidated, there are no specific treatment methods. Recent clinical and neuropathological evidence points to abnormalities in the development of the cerebral cortex, which are suggestive of defects in neuronal migration in some of these diseases. However, causal relationships between the genetic alterations present in patients, the migration defects during brain formation and the clinical features have not yet been established - a knowledge gap explored in the present proposal. Our work plan includes the analysis of genetically modified mice, as well as neural cells in 2D culture, brain organoids, and assembloids (3D models) derived from patients with an autism spectrum disorder, to evaluate cellular and molecular phenotypes of neuronal migration and to determine whether those pathologies can be corrected by gene therapy. We will also study the molecular mechanisms behind the neuronal migration defects, focusing on the role of Plexins/Semaphorins, Ephrins, and Reelin, three categories of chemotactic guidance molecules involved in neurodevelopment. We anticipate that the project will lead to significant innovation by identifying new pathological mechanisms in autism, selecting new molecular targets, and conducting proof-of-concept experiments that gene therapy can be successfully used for correcting the abnormal neural phenotypes. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

DE CARVALHO, LUCAS M.; CARVALHO, VINICIUS M. A.; CAMARGO, ANTONIO P.; PAPES, FABIO. Gene network analysis identifies dysregulated pathways in an autism spectrum disorder caused by mutations in Transcription Factor 4. SCIENTIFIC REPORTS, v. 15, n. 1, p. 15-pg., 2025-02-10. (20/11451-7, 22/12762-1, 19/12914-3, 18/04240-0)