Modeling PTEN overexpression-induced microcephaly in human brain organoids

• Published in: Molecular brain Vol. 14; no. 1; p. 131
• Main Authors: Dhaliwal, Navroop, Choi, Wendy W Y, Muffat, Julien, Li, Yun
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 30.08.2021; BioMed Central; BMC
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT; AKT protein; Analysis; Autism; Brain; Brain organoids; Cell Line; Chromosome 10; Dosage; Embryoid Bodies - drug effects; Gene Dosage; Gene Duplication; Genes, Reporter; Heterocyclic Compounds, 3-Ring - pharmacology; Human pluripotent stem cells; Humans; Kinases; Medical research; Medicine, Experimental; Micro Report; Microcephaly; Microcephaly - genetics; Microencephaly; Mutation; Neural precursors; Neural Stem Cells - drug effects; Neural Stem Cells - metabolism; Neurodevelopment; Neurodevelopmental disorders; Neurogenesis; Neurons; Organoids; Organoids - metabolism; Phenotypes; Phosphatases; Phosphatidylinositol 3-Kinases - physiology; Phosphorylation; Protein Processing, Post-Translational; Proto-Oncogene Proteins c-akt - antagonists & inhibitors; Proto-Oncogene Proteins c-akt - genetics; PTEN; PTEN Phosphohydrolase - biosynthesis; PTEN Phosphohydrolase - genetics; PTEN protein; Recombinant Fusion Proteins - metabolism; Signal Transduction; Stem cells; Tensin; Zika virus; Brain organoids; PTEN; AKT; Neurodevelopmental disorder; Human pluripotent stem cells; Microcephaly; Neural precursors
• ISSN: 1756-6606; 1756-6606
• DOI: 10.1186/s13041-021-00841-3

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.