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The tumor suppressor Pml regulates cell fate in the developing neocortex

Nature Neuroscience volume 12, pages 132–140 (2009)Cite this article

Abstract

The control of cell fate in neural progenitor cells is critical for nervous system development. Nevertheless, the processes involved are only partially known. We found that the expression of the tumor suppressor Pml was restricted to neural progenitor cells (NPCs) in the developing neocortex of the mouse. Notably, in Pml−/− cortices, the overall number of proliferating NPCs was increased and transition between the two major progenitor types, radial glial cells and basal progenitors, was impaired. This in turn resulted in reduced differentiation and an overall decrease in the thickness of the cortex wall. In NPCs, Pml regulated the subcellular distribution of the retinoblastoma protein (pRb) and the protein phosphatase 1α, triggering pRb dephosphorylation. Together, these findings reveal an unexpected role of Pml in controlling the function of NPCs in the CNS.

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Figure 1: Pml expression is confined to neural progenitor/stem cells.
Figure 2: Pml regulates the size of the cerebral cortex.
Figure 3: Pml controls proliferation and cell cycle exit in neuronal progenitors.
Figure 4: Pml loss skews the composition of neural progenitors subtypes in the developing neocortex.
Figure 5: Differentiation is impaired in Pml−/− cortices.
Figure 6: Pml-deficient NPCs show increased proliferation and impaired differentiation in vitro.
Figure 7: Pml colocalizes and interacts with pRb.
Figure 8: Pml-mediated control of PP1α-dependent dephosphorylation of pRb in the NPCs.

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Acknowledgements

A special thank to P.P. Pandolfi (Beth Israel Deaconess Cancer Center) and R. Hevner (Seattle Children's Hospital Research Institute) for the Pml−/− mouse line and the antibody to Tbr2, respectively. We particularly thank D. Dinsdale, J. Edwards and R. Edwards (Medical Research Council Toxicology Unit) for support and assistance with immunohistochemistry. We also thank C. Watson (University of Cambridge), D. Read, G. Melino, R. Knight, and M. Capasso (Medical Research Council Toxicology Unit) for critical discussions. P.S., P.N., T.R. and C.B. are supported by the Medical Research Council. C.B. is a PhD, student at the University of Leicester.

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  1. Cristian Bellodi

    Present address: Present address: Helen Diller Family Comprehensive Cancer Center, Box 0128, University of California San Francisco, San Francisco, California 94143-1270, USA.,

Authors and Affiliations

  1. Medicial Research Council Toxicology Unit, University of Leicester, Box 138, Lancaster Road, Leicester, LE1 7JL, UK

    Tarik Regad, Cristian Bellodi, Pierluigi Nicotera & Paolo Salomoni

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Contributions

T.R. and P.S. designed and performed the experiments. C.B. performed a number of experments. P.N. provided expertise and contributed to experimental design and discussion. T.R. contributed to the writing of the manuscript. P.S. supervised the research project and wrote the manuscript.

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Correspondence to Paolo Salomoni.

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Regad, T., Bellodi, C., Nicotera, P. et al. The tumor suppressor Pml regulates cell fate in the developing neocortex. Nat Neurosci 12, 132–140 (2009). https://doi.org/10.1038/nn.2251

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