Modeling PTEN overexpression-induced microcephaly in human brain organoids

Molecular Brain

Navroop Dhaliwal¹  Yun Li²  Wendy W.Y. Choi³  Julien Muffat⁴ 

[1] Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, 686 Bay Street, M5G 0A4, Toronto, ON, Canada;Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, 686 Bay Street, M5G 0A4, Toronto, ON, Canada;Department of Molecular Genetics, University of Toronto, 1 King’s College Circle, M5S 1A8, Toronto, ON, Canada;Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, 686 Bay Street, M5G 0A4, Toronto, ON, Canada;Department of Molecular Genetics, University of Toronto, 1 King’s College Circle, M5S 1A8, Toronto, ON, Canada;Program in Genetics and Genome Biology, The Hospital for Sick Children, 686 Bay Street, M5G 0A4, Toronto, ON, Canada;Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, 686 Bay Street, M5G 0A4, Toronto, ON, Canada;Department of Molecular Genetics, University of Toronto, 1 King’s College Circle, M5S 1A8, Toronto, ON, Canada;Program in Neurosciences and Mental Health, The Hospital for Sick Children, 686 Bay Street, M5G 0A4, Toronto, ON, Canada;

关键词: PTEN;    AKT;    Brain organoids;    Human pluripotent stem cells;    Neural precursors;    Microcephaly;    Neurodevelopmental disorder;   

DOI  :  10.1186/s13041-021-00841-3

来源: Springer

【 摘 要 】

The phosphatase and tensin homolog (PTEN) protein, encoded by the PTEN gene on chromosome 10, is a negative regulator of the phosphoinositide 3-kinase (PI3K) signaling pathway. Loss of PTEN has been linked to an array of human diseases, including neurodevelopmental disorders such as macrocephaly and autism. However, it remains unknown whether increased dosage of PTEN can lead to human disease. A recent human genetics study identifies chromosome 10 microduplication encompassing PTEN in patients with microcephaly. Here we generated a human brain organoid model of increased PTEN dosage. We showed that mild PTEN overexpression led to reduced neural precursor proliferation, premature neuronal differentiation, and the formation of significantly smaller brain organoids. PTEN overexpression resulted in decreased AKT activation, and treatment of wild-type organoids with an AKT inhibitor recapitulated the reduced brain organoid growth phenotypes. Together, our findings provide functional evidence that PTEN is a dosage-sensitive gene that regulates human neurodevelopment, and that increased PTEN dosage in brain organoids results in microcephaly-like phenotypes.

【 授权许可】

CC BY