Cortical neurons gradually attain a post-mitotic state.
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 α1 promoter (Tα1p). 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 down-regulated thereafter, associated with a concomitant up-regulation 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.
Center for Molecular Neurobiology Hamburg (ZMNH), University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany.|Department of Brain and Cognitive Sciences, Picower Institute for Learning and Memory, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Building 46, Room 4235A, Cambridge, MA 02139, USA.
Froylan Calderon de
FC
Anda
Department of Brain and Cognitive Sciences, Picower Institute for Learning and Memory, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Building 46, Room 4235A, Cambridge, MA 02139, USA.
Ram
R
Madabhushi
Department of Brain and Cognitive Sciences, Picower Institute for Learning and Memory, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Building 46, Room 4235A, Cambridge, MA 02139, USA.
Damien
D
Rei
Department of Brain and Cognitive Sciences, Picower Institute for Learning and Memory, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Building 46, Room 4235A, Cambridge, MA 02139, USA.|Department of Biological Sciences Xi'an Jiaotong-Liverpool University, 111 Renai Road, SIP Suzhou, Jiangsu 215123, China.
Jia
J
Meng
Department of Brain and Cognitive Sciences, Picower Institute for Learning and Memory, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Building 46, Room 4235A, Cambridge, MA 02139, USA.|Brain Mind Institute, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Bâtiment AI 2137.1, CH-1015 Lausanne, Switzerland.
Johannes
J
Gräff
Department of Brain and Cognitive Sciences, Picower Institute for Learning and Memory, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Building 46, Room 4235A, Cambridge, MA 02139, USA.
Omer
O
Durak
Department of Brain and Cognitive Sciences, Picower Institute for Learning and Memory, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Building 46, Room 4235A, Cambridge, MA 02139, USA.|Department of Neuroscience, Karolinska Institutet, Retzius väg 8, S-17177 Stockholm, Sweden.
Konstantinos
K
Meletis
Center for Molecular Neurobiology Hamburg (ZMNH), University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany.
Melanie
M
Richter
Center for Molecular Neurobiology Hamburg (ZMNH), University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany.
Birgit
B
Schwanke
Department of Brain and Cognitive Sciences, Picower Institute for Learning and Memory, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Building 46, Room 4235A, Cambridge, MA 02139, USA.
Alison
A
Mungenast
Department of Brain and Cognitive Sciences, Picower Institute for Learning and Memory, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Building 46, Room 4235A, Cambridge, MA 02139, USA.
Li-Huei
LH
Tsai
D000818:Animals; D001369:Axons / Q000187:drug effects / Q000378:metabolism; D002118:Calcium / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D048430:Cell Shape / Q000187:drug effects; D002540:Cerebral Cortex / Q000166:cytology*; D003712:Dendrites / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008938:Mitosis / Q000187:drug effects; D055495:Neurogenesis / Q000187:drug effects; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects
D002118:Calcium