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