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Postnatal loss of Dlk1 imprinting in stem cells and niche astrocytes regulates neurogenesis

Nature volume 475, pages 381–385 (2011)Cite this article

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Abstract

The gene for the atypical NOTCH ligand delta-like homologue 1 (Dlk1) encodes membrane-bound and secreted isoforms that function in several developmental processes in vitro and in vivo. Dlk1, a member of a cluster of imprinted genes, is expressed from the paternally inherited chromosome1,2. Here we show that mice that are deficient in Dlk1 have defects in postnatal neurogenesis in the subventricular zone: a developmental continuum that results in depletion of mature neurons in the olfactory bulb. We show that DLK1 is secreted by niche astrocytes, whereas its membrane-bound isoform is present in neural stem cells (NSCs) and is required for the inductive effect of secreted DLK1 on self-renewal. Notably, we find that there is a requirement for Dlk1 to be expressed from both maternally and paternally inherited chromosomes. Selective absence of Dlk1 imprinting in both NSCs and niche astrocytes is associated with postnatal acquisition of DNA methylation at the germ-line-derived imprinting control region. The results emphasize molecular relationships between NSCs and the niche astrocyte cells of the microenvironment, identifying a signalling system encoded by a single gene that functions coordinately in both cell types. The modulation of genomic imprinting in a stem-cell environment adds a new level of epigenetic regulation to the establishment and maintenance of the niche, raising wider questions about the adaptability, function and evolution of imprinting in specific developmental contexts.

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Figure 1: DLK1 regulates postnatal neurogenesis.
Figure 2: DLK1 is secreted by postnatal SVZ niche astrocytes.
Figure 3: NSCs require membrane-bound DLK1 to respond to niche-secreted DLK1.
Figure 4: NSCs and niche astrocytes selectively lose Dlk1 imprinting postnatally.

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Acknowledgements

We are grateful to J. Herbert and E. B. Keverne for sharing expertise during the course of this work. We thank members of the Ferguson-Smith laboratory for discussions and B. Sun, D. Gray, S. Curran, I. Gutteridge, R. Rancourt and X. d’Anglemont de Tassigny for technical assistance. The work was funded by grants from the Medical Research Council and Wellcome Trust to A.C.F.-S. and by grants from Ministerio de Ciencia e Innovación (SAF2008-01006, CB06/05/0086, RD06/0010/0010) and Generalitat Valenciana (Prometeo) to I.F. S.R.F. is a recipient of a University of Cambridge Herchel-Smith Fellowship.

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Author notes

  1. Marika Charalambous and Elizabeth Radford: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Physiology, Development & Neuroscience, University of Cambridge, Cambridge CB2 3EG, UK,

    Sacri R. Ferrón, Marika Charalambous, Elizabeth Radford, Kirsten McEwen, Eleanor Hind & Anne C. Ferguson-Smith

  2. Department of Molecular Neurobiology, National Institute for Medical Research, Medical Research Council, London NW7 1AA, UK,

    Hendrik Wildner & Francois Guillemot

  3. Departamento de Biología Celular, Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas, Universidad de Valencia, 46100 Burjassot, Spain,

    Jose Manuel Morante-Redolat & Isabel Fariñas

  4. Department of Inorganic and Organic Chemistry and Biochemistry, Medical School, Regional Center for Biomedical Research, University of Castilla-La Mancha, Avenida de Almansa 14, 02006 Albacete, Spain,

    Jorge Laborda

  5. Division of Cellular and Gene Therapies, Cellular and Tissue Therapies Branch, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892, USA,

    Steven R. Bauer

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  1. Sacri R. Ferrón
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Contributions

S.R.F. conceived and performed experiments and developed the project, coordinated collaborations and wrote the manuscript. M.C. conducted methylation experiments, helped to design experiments, contributed ideas and interpreted results. E.R. performed expression analysis, contributed to ideas and interpreted results. K.M. helped with imprinting and methylation studies. H.W. and F.G. designed and performed embryo studies. E.H. helped with imprinting and NOTCH-expression studies. J.M.M.-R. performed the NOTCH-pathway experiments. J.L. and S.R.B. provided the Dlk1−/− mouse. I.F. contributed ideas, discussed results and helped to write the manuscript. A.C.F.-S. conceived and developed the project, designed experiments, interpreted results, coordinated collaborations, contributed ideas and funds and wrote the manuscript.

Corresponding author

Correspondence to Anne C. Ferguson-Smith.

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The authors declare no competing financial interests.

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Ferrón, S., Charalambous, M., Radford, E. et al. Postnatal loss of Dlk1 imprinting in stem cells and niche astrocytes regulates neurogenesis. Nature 475, 381–385 (2011). https://doi.org/10.1038/nature10229

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