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HMGA regulates the global chromatin state and neurogenic potential in neocortical precursor cells

Nature Neuroscience volume 15, pages 1127–1133 (2012)Cite this article

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Abstract

Neural precursor cells (NPCs) in the mouse neocortex generate various neuronal and glial cell types in a developmental stage–dependent manner. Most NPCs lose their neurogenic potential during development, although the underlying mechanisms of this process are not fully understood. We found that the chromatin of mouse NPCs gradually becomes more condensed and less dynamic on a global scale during neocortical development. Furthermore, we found high mobility group A (HMGA) proteins to be essential for the open chromatin state of NPCs at early developmental stages. Knockdown of HMGA proteins in early-stage NPCs reduced their neurogenic potential. Conversely, overexpression of HMGA proteins conferred neurogenic potential on late-stage NPCs, an effect that was antagonized by coexpression of a histone H1 mutant that inhibits chromatin opening. Thus, HMGA proteins contribute to the neurogenic potential of NPCs in the early stages of neocortical development, possibly through induction of an open chromatin state.

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Figure 1: Chromatin state in NPCs becomes condensed globally during mouse neocortical development.
Figure 2: HMGA proteins are important for global opening of the chromatin state in early-stage NPCs.
Figure 3: HMGA proteins are essential for the neurogenic potential of early-stage NPCs in vitro.
Figure 4: HMGA proteins are important for the neurogenic potential of NPCs in vivo.
Figure 5: HMGA proteins inhibit astrocyte differentiation of early-stage NPCs in vivo.
Figure 6: Expression of H1cc inhibits the promotion of neuronal differentiation by HMGA overexpression in vivo.

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Acknowledgements

We thank C.L. Cepko (Harvard University), T. Matsuda (Kyoto University), T. Kitamura (The University of Tokyo), M. Nakafuku (Cincinnati Children's Hospital Medical Center and University of Cincinnati), H. Song (Johns Hopkins University) and H. Okano (Keio University) for plasmids, K. Ohsumi (Nagoya University) for antibodies, K. Tyssowski and E. Nigh for editing the manuscript, H. Okano for Nes-d4Venus mice, A. Miyajima for FACS, and members of the Gotoh laboratory for helpful discussion. This work was supported by Grants-in-Aid for Scientific Research (A) from the Ministry of Education, Culture, Sports, Science, and Technology (MEXT) of Japan, Innovative Areas “Neural Diversity and Neocortical Organization” of MEXT, by Core Research for Evolutional Science and Technology of the Japan Science and Technology Agency, by the Japan Society for the Promotion of Science, and by the Global COE Program “Integrative Life Science Based on the Study of Biosignaling Mechanisms” of MEXT.

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  1. Yusuke Kishi and Yuki Fujii: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo, Japan

    Yusuke Kishi, Yuki Fujii, Yusuke Hirabayashi & Yukiko Gotoh

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  1. Yusuke Kishi
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  2. Yuki Fujii
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Contributions

Y.K., Y.F., Y.H. and Y.G. designed the study. Y.K. and Y.F. carried out the experiments and analyzed the data. Y.H. supported the experiments. Y.K. and Y.G. wrote the manuscript. Y.G. supervised the study.

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Correspondence to Yukiko Gotoh.

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Kishi, Y., Fujii, Y., Hirabayashi, Y. et al. HMGA regulates the global chromatin state and neurogenic potential in neocortical precursor cells. Nat Neurosci 15, 1127–1133 (2012). https://doi.org/10.1038/nn.3165

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