Rem2 GTPase controls proliferation and apoptosis of neurons during embryo development

We have recently found that Rem2 GTPase, highly expressed in human embryonic stem cells (hESC), maintains the cell cycle and controls proper differentiation towards ectoderm, suggesting a role in neuronal development. We describe here the use of the zebrafish (Danio rerio) model to determine the physiological significance of Rem2 during embryogenesis. We show that Rem2 RNA is highly expressed in zebrafish embryos up to 2 hours of development followed by a decrease in expression until 48 hours when afterwards Rem2 is switched on again until 5 days. In situ expression analysis reveals that Rem2 is expressed exclusively in the tectum of the brain and eye of the zebrafish. Rem2 morpholino demonstrates impaired embryo development resulting in loss of neural tissue. We show that the mechanism of action of Rem2 is to control apoptosis and proliferation, peaking at 36 hours of development. Rem2 is down-regulated under general differentiation conditions of hESC and is lower expressed in most differentiated cells; however, it is upregulated with neuronal development. This suggests that Rem2 is critical for neuronal development during embryogenesis by regulating proliferation and apoptosis. We propose a model in which Rem2 GTPase is a key regulator maintaining pluripotency during early stages of embryogenesis and survival of neurons during later embryonic development.