RB controls growth, survival, and neuronal migration in human cerebral organoids [RESEARCH ARTICLE]

Takeshi Matsui, Vanesa Nieto-Estevez, Sergii Kyrychenko, Jay W. Schneider, and Jenny Hsieh

Retinoblastoma (RB) is a tumor suppressor gene which regulates cell cycle entry to S phase via E2F transcription factors. Using knockout (KO) mice, it has been described that Rb plays a role in cell migration and differentiation in developing and adult brain as well as apoptosis. In addition, the RB family is required for the self-renewal and survival of human embryonic stem cells (ESCs). However, little is known about the role of this gene in human brain development. Here, we investigated the role of RB in cerebral organoids from human ESCs deficient for RB. We showed that RB is expressed abundantly in neural stem/progenitor cells in organoids at 15 and 28 days in culture. Our results revealed that the loss of RB promotes S phase entry of DCX⁺ cells and increases apoptosis of Sox2⁺ neural stem/progenitor cells, DCX⁺ and Tuj1⁺ neurons, which was associated with the upregulation of CYCLIN A2 and BAX genes. Moreover, we observed aberrant Tuj1⁺ neuronal migration in RB-KO organoids, and upregulation of the VLDLR gene, a receptor important in Reelin signaling. Interestingly, ectopically localized Tuj1⁺ cells were also found in teratomas from RB-KO human ESCs. These results suggest that RB gene has critical roles in human brain development.

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