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Proliferation of hippocampal progenitors relies on p27-dependent regulation of Cdk6 kinase activity

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Abstract

Neural stem cells give rise to granule dentate neurons throughout life in the hippocampus. Upon activation, these stem cells generate fast proliferating progenitors that complete several rounds of divisions before differentiating into neurons. Although the mechanisms regulating the activation of stem cells have been intensively studied, little attention has been given so far to the intrinsic machinery allowing the expansion of the progenitor pool. The cell cycle protein Cdk6 positively regulates the proliferation of hippocampal progenitors, but the mechanism involved remains elusive. Whereas Cdk6 functions primarily as a cell cycle kinase, it can also act as transcriptional regulator in cancer cells and hematopoietic stem cells. Using mouse genetics, we show here that the function of Cdk6 in hippocampal neurogenesis relies specifically on its kinase activity. The present study also reveals a specific regulatory mechanism for Cdk6 in hippocampal progenitors. In contrast to the classical model of the cell cycle, we observe that the Cip/Kip family member p27, rather than the Ink4 family, negatively regulates Cdk6 in the adult hippocampus. Altogether, our data uncover a unique, cell type-specific regulatory mechanism controlling the expansion of hippocampal progenitors, where Cdk6 kinase activity is modulated by p27.

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Abbreviations

AC3:

Activated caspase 3

DG:

Dentate gyrus

SGZ:

Subgranular zone

Rb:

Retinoblastoma protein

Cdk:

Cyclin-dependent kinase

CKI:

Cyclin-dependent kinase inhibitors

BrdU:

Bromodeoxyuridine

PFA:

Paraformaldehyde

PBS:

Phosphate-buffered saline

DAPI:

4′,6-Diamidino-2-phenylindole

SVZ:

Subventricular zone

PVDF:

Polyvinylidene difluoride

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Acknowledgements

We thank Pierre-Bernard Van Lerberghe for his technical assistance. LN and BM are, respectively, Senior Research Associate and Research Director of the Belgian National Funds for Scientific Research (FRS-FNRS). RV was a postdoctoral researcher of FRS-FNRS. NC and QM were research fellows with the Belgian Fund for Research in Industry and Agriculture (FNRS-FRIA). EG was supported by Marie Curie Action (Cofund) within the EU FP7 program. BM was funded by grants from the FRS-FNRS, the Fonds Léon Fredericq, the Fondation Médicale Reine Elisabeth, Belspo and the Belgian Science Policy (IAP-VII network P7/07).

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Authors and Affiliations

  1. Laboratory of Developmental Neurobiology, GIGA-Neurosciences, Quartier Hôpital, University of Liège, Avenue Hippocrate 15, B36 +1, 4000, Liège, Belgium

    Nicolas Caron, Emmanuelle C. Genin, Quentin Marlier, Sébastien Verteneuil, Pierre Beukelaers, Renaud Vandenbosch & Brigitte Malgrange

  2. Molecular Regulation of Neurogenesis, GIGA-Neurosciences, University of Liège, Liège, Belgium

    Laurent Nguyen

  3. Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL, USA

    Laurence Morel

  4. Molecular Oncology Research Institute, Tufts Medical Center, 75 Kneeland Street, Boston, MA, USA

    Miaofen G. Hu & Philip W. Hinds

  5. Department of Developmental, Molecular, and Chemical Biology, Tufts University School of Medicine, Boston, MA, USA

    Philip W. Hinds

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  1. Nicolas Caron
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  2. Emmanuelle C. Genin
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  3. Quentin Marlier
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  4. Sébastien Verteneuil
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  9. Laurent Nguyen
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Contributions

NC, EG, RV and BM designed the concept of the experiments. NC, EG, RV, QM, SV, PB, LN and BM collected data and performed data analysis/interpretation. MGH, PH and LM provided study material. RV and BM wrote the manuscript. BM provided financial support.

Corresponding author

Correspondence to Brigitte Malgrange.

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The authors declare no competing financial interest.

Additional information

Nicolas Caron and Emmanuelle C. Genin: co-first authors.

Renaud Vandenbosch and Brigitte Malgrange: co-last authors.

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Caron, N., Genin, E.C., Marlier, Q. et al. Proliferation of hippocampal progenitors relies on p27-dependent regulation of Cdk6 kinase activity. Cell. Mol. Life Sci. 75, 3817–3827 (2018). https://doi.org/10.1007/s00018-018-2832-x

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