Modeling Rett Syndrome With Human Patient-Specific Forebrain Organoids

Ana Rita Gomes; Tiago G Fernandes; Sandra H Vaz; Teresa P Silva; Evguenia P Bekman; Sara Xapelli; Sofia Duarte; Mehrnaz Ghazvini; Joost Gribnau; Alysson R Muotri; Cleber A Trujillo; Ana M Sebastião; Joaquim M S Cabral; Maria Margarida Diogo

doi:10.3389/fcell.2020.610427

Modeling Rett Syndrome With Human Patient-Specific Forebrain Organoids

Front Cell Dev Biol. 2020 Dec 10:8:610427. doi: 10.3389/fcell.2020.610427. eCollection 2020.

Authors

Ana Rita Gomes^{1

2}, Tiago G Fernandes¹, Sandra H Vaz^{2

3}, Teresa P Silva^{1

2}, Evguenia P Bekman^{1

2

4}, Sara Xapelli^{2

3}, Sofia Duarte⁵, Mehrnaz Ghazvini⁶, Joost Gribnau⁷, Alysson R Muotri^{8

9

10

11

12}, Cleber A Trujillo^{8

9

10}, Ana M Sebastião^{2

3}, Joaquim M S Cabral¹, Maria Margarida Diogo¹

Affiliations

¹ Department of Bioengineering and iBB-Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal.
² Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.
³ Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.
⁴ The Discoveries Centre for Regenerative and Precision Medicine (Lisbon Campus), Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal.
⁵ Department of Pediatric Neurology, Centro Hospitalar Universitário de Lisboa Central, Lisbon, Portugal.
⁶ Erasmus MC iPS Facility, Erasmus Medical Center, University Medical Center, Rotterdam, Netherlands.
⁷ Department of Developmental Biology, Erasmus Medical Center, University Medical Center, Rotterdam, Netherlands.
⁸ Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, CA, United States.
⁹ Rady Children's Hospital San Diego, School of Medicine, University of California, San Diego, La Jolla, CA, United States.
¹⁰ Department of Cellular and Molecular Medicine, School of Medicine, University of California, San Diego, La Jolla, CA, United States.
¹¹ Kavli Institute for Brain and Mind, University of California, San Diego, La Jolla, CA, United States.
¹² Center for Academic Research and Training in Anthropogeny, La Jolla, CA, United States.

Abstract

Engineering brain organoids from human induced pluripotent stem cells (hiPSCs) is a powerful tool for modeling brain development and neurological disorders. Rett syndrome (RTT), a rare neurodevelopmental disorder, can greatly benefit from this technology, since it affects multiple neuronal subtypes in forebrain sub-regions. We have established dorsal and ventral forebrain organoids from control and RTT patient-specific hiPSCs recapitulating 3D organization and functional network complexity. Our data revealed a premature development of the deep-cortical layer, associated to the formation of TBR1 and CTIP2 neurons, and a lower expression of neural progenitor/proliferative cells in female RTT dorsal organoids. Moreover, calcium imaging and electrophysiology analysis demonstrated functional defects of RTT neurons. Additionally, assembly of RTT dorsal and ventral organoids revealed impairments of interneuron's migration. Overall, our models provide a better understanding of RTT during early stages of neural development, demonstrating a great potential for personalized diagnosis and drug screening.

Keywords: Rett syndrome; disease modeling; forebrain; human induced pluripotent stem cells; neurodevelopmental disorders; organoids.