Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Control of neurulation by the nucleosome assembly protein-1–like 2

Nature Genetics volume 25, pages 431–435 (2000)Cite this article

Abstract

Neurulation is a complex process of histogenesis involving the precise temporal and spatial organization of gene expression1,2. Genes influencing neurulation include proneural genes determining primary cell fate, neurogenic genes involved in lateral inhibition pathways and genes controlling the frequency of mitotic events. This is reflected in the aetiology and genetics of human and mouse neural tube defects, which are of both multifactorial and multigenic origin3. The X-linked gene Nap1l2, specifically expressed in neurons, encodes a protein that is highly similar to the nucleosome assembly (NAP) and SET proteins. We inactivated Nap1l2 in mice by gene targeting, leading to embryonic lethality from mid-gestation onwards. Surviving mutant chimaeric embryos showed extensive surface ectoderm defects as well as the presence of open neural tubes and exposed brains similar to those observed in human spina bifida and anencephaly. These defects correlated with an overproduction of neuronal precursor cells. Protein expression studies showed that the Nap1l2 protein binds to condensing chromatin during S phase and in apoptotic cells, but remained cytoplasmic during G1 phase. Nap1l2 therefore likely represents a class of tissue-specific factors interacting with chromatin to regulate neuronal cell proliferation.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Localization of Nap1l2 mRNAs in the mouse nervous system by in situ hybridization with oligonucleotide probes.
Figure 2: Chimaeric, retarded and resorbed embryos at different time points during mouse development.
Figure 3: Mutant chimaeric embryos obtained from morula aggregation experiments.
Figure 4: Sections of lacZ-stained embryos with specific phenotypes.
Figure 5: ES cells from the mutant ES cell line 5b17 differentiate in vitro into neurons.
Figure 6: P19 cells transfected with the expression vector pEGFP express GFP–Nap1l2 fusion proteins under the control of the CMV promoter (a–c).

Similar content being viewed by others

References

  1. Kerszberg, M. & Changeux, J.-P. A simple molecular model of neurulation. Bioessays 20, 758–770 (1998).

    Article  CAS  Google Scholar 

  2. Wilson, P.A. & Hemmati-Brivanlou, A. Vertebrate neural induction: inducers, inhibitors, and a new synthesis. Neuron 18, 699–710 (1997).

    Article  CAS  Google Scholar 

  3. Emery, A.E.H. in Methodology in Medical Genetics 58 (Churchill Livingstone, Edinburgh, 1986).

    Google Scholar 

  4. Altman, R. & Kellog, D. Control of mitotic events by Nap1 and Gin4 kinase. J. Cell Biol. 138, 119–130 (1997).

    Article  CAS  Google Scholar 

  5. Simon, H.U. et al. Molecular characterization of hNRP, a cDNA encoding a human nucleosome-assembly-protein-I-related gene product involved in the induction of cell proliferation. Biochem. J. 297, 389–397 (1994).

    Article  CAS  Google Scholar 

  6. Laskey, R.A., Honda, B.M., Mills, A.D. & Finch, J.T. Nucleosomes are assembled by an acidic protein which binds histones and transfers them to DNA. Nature 275, 416–420 (1978).

    Article  CAS  Google Scholar 

  7. McQuibban, G.A., Commisso-Cappelli, C.N. & Lewis, P.N. Assembly, remodeling, and histone binding capabilities of yeast nucleosome assembly protein 1. J. Biol. Chem. 273, 6582–6590 (1998).

    Article  CAS  Google Scholar 

  8. Ito, T., Bulger, M., Kobayashi, R. & Kadonaga, J.T. Drosophila NAP-1 is a core histone chaperone that functions in ATP-facilitated assembly of regularly spaced nucleosomal arrays. Mol. Cell. Biol. 16, 3112–3124 (1996).

    Article  CAS  Google Scholar 

  9. Rodriguez, P. et al. Functional characterization of human nucleosome assembly protein-2 (NAP1L4) suggests a role as a histone chaperone. Genomics 44, 253–265 (1997).

    Article  CAS  Google Scholar 

  10. Kellogg, D.R., Kikuchi, A., Fujii-Nakata, T., Turck, C.W. & Murray, A.W. Members of the NAP/SET family of proteins interact specifically with B-type cyclins. J. Cell Biol. 130, 661–673 (1995).

    Article  CAS  Google Scholar 

  11. Rougeulle, C. & Avner, P. Cloning and characterization of a murine brain specific gene Bpx and its human homologue lying within the Xic candidate region. Hum. Mol. Genet. 5, 41–49 (1996).

    Article  CAS  Google Scholar 

  12. Fraichard, A. et al. In vitro differentiation of embryonic stem cells into glial cells and functional neurons. J. Cell Sci. 108, 3181–3188 (1995).

    CAS  PubMed  Google Scholar 

  13. Struebing, C. et al. Differentiation of pluripotent embryonic stem cells into the neuronal lineage in vitro gives rise to mature inhibitory and excitatory neurons. Mech. Dev. 53, 275–287 (1995).

    Article  CAS  Google Scholar 

  14. McBurney, M.W. P19 embryonal carcinoma cells. Int. J. Dev. Biol. 37, 135–140 (1993).

    CAS  PubMed  Google Scholar 

  15. Naruse, I. & Keino, H. Apoptosis in the developing CNS. Prog. Neurobiol. 47, 135–155 (1995).

    Article  CAS  Google Scholar 

  16. Khochbin, S. & Wolffe, A.P. Developmentally regulated expression of linker-histone variants in vertebrates. Eur. J. Biochem. 225, 501–510 (1994).

    Article  CAS  Google Scholar 

  17. Reyes, J.C. et al. Altered control of cellular proliferation in the absence of mammalian brahma (SNF2α). EMBO J. 17, 6979–6991 (1998).

    Article  CAS  Google Scholar 

  18. Ishibashi, M. et al. Targeted disruption of mammalian hairy and Enhancer of split homolog-1 (HES-1) leads to up-regulation of neural helix-loop-helix factors, premature neurogenesis, and severe neural tube defects. Genes Dev. 9, 3136–3148 (1995).

    Article  CAS  Google Scholar 

  19. Wilson, D.B. Proliferation in the neural tube of the Splotch (Sp) mutant mouse. J. Comp. Neurol. 154, 249–256 (1974).

    Article  CAS  Google Scholar 

  20. Jensson, O. et al. A family showing apparent X linked inheritance of both anencephaly and spina bifida. J. Med. Genet. 25, 227–229 (1988).

    Article  CAS  Google Scholar 

  21. Neumann, P.E. et al. Multifactorial inheritance of neural tube defects: localization of the major gene and recognition of modifiers in ct mutant mice. Nature Genet. 6, 357–362 (1994).

    Article  CAS  Google Scholar 

  22. Copp, A.J., Checiu, I. & Henson, J.N. Developmental basis of severe neural tube defects in the loop-tail (Lp) mutant mouse: Use of microsatellite DNA markers to identify embryonic genotype. Dev. Biol. 165, 20–29 (1994).

    Article  CAS  Google Scholar 

  23. Young, W.S. 3d, Bonner, T.I. & Brann, M.R. Mesencephalic dopamine neurons regulate the expression of neuropeptide mRNAs in the rat forebrain. Proc. Natl Acad. Sci. USA 83, 9827–9831 (1986).

    Article  CAS  Google Scholar 

  24. Le Novère, N., Zoli, M. & Changeux, J.P. Neuronal nicotinic receptor alpha 6 subunit mRNA is selectively concentrated in catecholaminergic nuclei of the rat brain. Eur. J. Neurosci. 8, 2428–2439 (1996).

    Article  Google Scholar 

  25. Rougeulle, C., Colleaux, L., Dujon, B. & Avner, P. Generation and characterization of an ordered λ clone array for the 460-kb region surrounding the murine Xist sequence. Mamm. Genome 5, 416–423 (1994).

    Article  CAS  Google Scholar 

  26. Gardner, R.L. Mouse chimeras obtained by the injection of cells into the blastocyst. Nature 220, 596–597 (1968).

    Article  CAS  Google Scholar 

  27. Wood, S.A. et al. Simple and efficient production of embryonic stem cell-embryo chimeras by coculture. Proc. Natl Acad. Sci. USA 90, 4582–4585 (1993).

    Article  CAS  Google Scholar 

  28. Nagy, A., Rossant, J., Nagy, R., Abramow-Newerly, W. & Roder, J.C. Derivation of completely cell culture-derived mice from early-passage embryonic stem cells. Proc. Natl Acad. Sci. USA 90, 8424–8428 (1993).

    Article  CAS  Google Scholar 

  29. Papenbrock, T. et al. Murine Hoxc-9 gene contains a structurally and functionally conserved enhancer. Dev. Dyn. 12, 540–547 (1998).

    Article  Google Scholar 

  30. Hogan, B., Beddington, R., Costantini, F. & Lacy, E. in Manipulation of the Mouse Embryo 373–375 (Cold Spring Harbor Laboratory Press, New York, 1994).

    Google Scholar 

Download references

Acknowledgements

We thank Y. Gong for technical assistance; C. Rougeulle for DNA probes; M. Cohen-Tannoudji for the lacZneo cassette; A. Copp and P. Stanier for comments concerning the mutant phenotypes; A. Prochiantz and D. Riethmacher for advice on antibodies; and E. Heard for critical reading of the manuscript. U.C.R. has been supported by grants from the Deutsche Forschungsgemeinschaft, the AFM and the EEC (contract no. BMH4-CT98-5072). D.D.S. was supported for this research by URRF Gene Targeting/Knockout Mouse Facility funding. N.L. was financed by the Ministère de la Recherche et de l'Enseignement, AFM and the Pasteur Institute J.P.C. was supported by the Collège de France and AFM.

Author information

Authors and Affiliations

  1. Génétique Moléculaire Murine CNRS URA 1947, Institut Pasteur, Paris Cedex, 15, France

    Ute C. Rogner & Philip Avner

  2. Neurobiologie Moléculaire CNRS URA 1284, Institut Pasteur, Paris Cedex, 15, France

    Nicolas Le Novère & Jean-Pierre Changeux

  3. Center for Molecular and Structural Biology, Medical University of South Carolina, Charleston, South Carolina, USA

    Demetri D. Spyropoulos

Authors
  1. Ute C. Rogner
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Demetri D. Spyropoulos
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nicolas Le Novère
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jean-Pierre Changeux
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Philip Avner
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ute C. Rogner.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rogner, U., Spyropoulos, D., Le Novère, N. et al. Control of neurulation by the nucleosome assembly protein-1–like 2. Nat Genet 25, 431–435 (2000). https://doi.org/10.1038/78124

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/78124

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing