Cortical neurons gradually attain a post-mitotic state

• Published in: Cell research 2016-09, Vol.26 (9), p.1033-1047
• Main Authors: Anda, Froylan Calderon de, Madabhushi, Ram, Rei, Damien, Meng, Jia, Gräff, Johannes, Durak, Omer, Meletis, Konstantinos, Richter, Melanie, Schwanke, Birgit, Mungenast, Alison, Tsai, Li-Huei
• Format: Article
• Language: English
• Subjects: 631/378/1697; 631/378/2620/2618; 631/80/641/1655; 631/80/86/1999; Animals; Axons - drug effects; Axons - metabolism; Biomedical and Life Sciences; Calcium; Calcium - pharmacology; Cell Biology; Cell Differentiation - drug effects; Cell Nucleus - drug effects; Cell Nucleus - metabolism; Cell Proliferation - drug effects; Cell Shape - drug effects; Cerebral Cortex - cytology; Dendrites - drug effects; Dendrites - metabolism; Life Sciences; Medicin och hälsovetenskap; Mice; Mitosis - drug effects; Neurogenesis - drug effects; Neurons - cytology; Neurons - drug effects; Neurons - metabolism; Original; original-article; Transcription, Genetic - drug effects
• ISSN: 1001-0602; 1748-7838; 1748-7838
• DOI: 10.1038/cr.2016.76

Once generated, neurons are thought to permanently exit the cell cycle and become irreversibly differentiated. However, neither the precise point at which this post-mitotic state is attained nor the extent of its irreversibility is clearly defined. Here we report that newly born neurons from the upper layers of the mouse cortex, despite initiating axon and dendrite elongation, continue to drive gene expression from the neural progenitor tubulin al promoter （Talp）. These observations suggest an ambiguous post-mitotic neuronal state. Whole transcriptome analysis of sorted upper cortical neurons further revealed that neurons continue to express genes related to cell cycle progression long after mitotic exit until at least post-natal day 3 （P3）. These genes are however downregulated thereafter, associated with a concomitant upregulation of tumor suppressors at P5. Interestingly, newly born neurons located in the cortical plate （CP） at embryonic day 18-19 （E18-E19） and P3 challenged with calcium influx are found in S/G2/M phases of the cell cycle, and still able to undergo division at E18-E19 but not at P3. At P5 however, calcium influx becomes neurotoxic and leads instead to neuronal loss. Our data delineate an unexpected flexibility of cell cycle control in early born neurons, and describe how neurons transit to a post-mitotic state.