Requirement for COUP-TFI and II in the temporal specification of neural stem cells in CNS development

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Abstract

In the developing CNS, subtypes of neurons and glial cells are generated according to a schedule that is defined by cell-intrinsic mechanisms that function at the progenitor-cell level. However, no critical molecular switch for the temporal specification of CNS progenitor cells has been identified. We found that chicken ovalbumin upstream promoter-transcription factor I and II (Coup-tfI and Coup-tfII, also known as Nr2f1 and Nr2f2) are required for the temporal specification of neural stem/progenitor cells (NSPCs), including their acquisition of gliogenic competence, as demonstrated by their responsiveness to gliogenic cytokines. COUP-TFI and II are transiently co-expressed in the ventricular zone of the early embryonic CNS. The double knockdown of Coup-tfI/II in embryonic stem cell (ESC)-derived NSPCs and the developing mouse forebrain caused sustained neurogenesis and the prolonged generation of early-born neurons. These findings reveal a part of the timer mechanisms for generating diverse types of neurons and glial cells during CNS development.

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Figure 1: Coup-tfI/II double knockdown inhibits the neurogenic-to-gliogenic transition in vitro.
Figure 2: Coup-tfI/II knockdown phenotype is rescued by expression of knockdown-resistant mutant COUP-TFI/II.
Figure 3: Coup-tfI/II are required to free Gfap promoter from epigenetic silencing and to confer responsiveness to gliogenic cytokines.
Figure 4: Coup-tfI/II are involved in the temporal restriction of NSPC neuropotency.
Figure 5: Coup-tfI/II knockdown inhibits initiation of gliogenesis in developing forebrain.
Figure 6: Coup-tfI/II knockdown inhibits temporal specification of NSPCs in developing forebrain.
Figure 7: Transcriptional repressor function of Coup-tfI/II is required for temporal specification of NSPCs.

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Acknowledgements

We are grateful to H. Miyoshi (Riken BioResource Center) for the lentivirus constructs, R.F. Hevner (University of Washington) for the antibody to Tbr1, S. Mitani (Tokyo Women's Medical University) for the antibody to GFP (mFX73) and K. Shimamura (Kumamoto University) for the Vp16 and Drosophila engrailed constructs. We also thank the members of the Okano laboratory for discussion, technical advice and/or critical reading of the manuscript. This study was supported by Core Research for Evolutional Science Technology/Solution-Oriented Research for Science and Technology–Japan Science and Technology Agency (H.O.), grants-in-aid for scientific research from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) in Japan (T.S. and H.O.), a grant-in-aid from the 21st Century Center Of Excellence program of MEXT to Keio University, a Keio University grant-in-aid for encouragement of young medical scientists (H.N.), and a grant-in-aid for Japan Society for the Promotion of Science Fellows (H.N.).

Author information

All experiments were designed by T.S. and H.N. T.S. guided the experimental processes. Most of the experiments and data analyses were carried out by H.N. Some parts of the in vitro culture assay and immunostaining were performed by S.N. S.N. also assisted with all the experiments. The project was supervised by T.S. and H.O.

Correspondence to Takuya Shimazaki or Hideyuki Okano.

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Supplementary Text and Figures

Supplementary Figures 1–8, Supplementary Tables 1 and 2, and Supplementary Methods (PDF 907 kb)

Supplementary Movie 1

Ectopically induced Tbr1-positive neurons by high-dose knockdown lentivirus infection showed abnormal multipolar morphology. Three-dimensional video image corresponding to Supplementary Fig. 6c. (MOV 8726 kb)

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Naka, H., Nakamura, S., Shimazaki, T. et al. Requirement for COUP-TFI and II in the temporal specification of neural stem cells in CNS development. Nat Neurosci 11, 1014–1023 (2008) doi:10.1038/nn.2168

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