The bHLH gene Hes1 as a repressor of the neuronal commitment of CNS stem cells

Yuki Nakamura, Shin Ichi Sakakibara, Takaki Miyata, Masaharu Ogawa, Takuya Shimazaki, Samuel Weiss, Ryoichiro Kageyama, Hideyuki Okano

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258 Citations (Scopus)

Abstract

Hes1 is one of the basic helix-loop-helix transcription factors that regulate mammalian CNS development, and its loss- and gain-of-function phenotypes indicate that it negatively regulates neuronal differentiation. Here we report that Has1(-/-) mice expressed both early (TuJ1 and Hu) and late (MAP2 and Neurofilament) neuronal markers prematurely, and that there were approximately twice the normal number of neurons in the Hes1 (-/-) brain during early neural development. However, immunochemical analyses of sections and dissociated cells using neural progenitor markers, including nestin, failed to detect any changes in Hes1 (-/-) progenitor population. Therefore, further characterization of neural progenitor cells that discriminated between multipotent and monopotent cells was performed using two culture methods, low-density culture, and a neurosphere assay. We demonstrate that the self-renewal activity of multipotent progenitor cells was reduced in the Hes1 (-/-) brain, and that their subsequent commitment to the neuronal lineage was accelerated. The Hes1 (-/-) neuronal progenitor cells were functionally abnormal, in that they divided, on average, only once, and then generated two neurons, (instead of one progenitor cell and one neuron), whereas wild-type progenitor cells divided more. In addition, some Hes1(-/-) progenitors followed an apoptotic fate. The overproduction of neurons in the early Hes1(-/-) brains may reflect this premature and immediate generation of neurons as well as a net increase in the number of neuronal progenitor cells. Taken together, we conclude that Hes1 is important for maintaining the self- renewing ability of progenitors and for repressing the commitment of multipotent progenitor cells to a neuronal fate, which is critical for the correct number of neurons to be produced and for the establishment of normal neuronal function.

Original languageEnglish
Pages (from-to)283-293
Number of pages11
JournalJournal of Neuroscience
Volume20
Issue number1
DOIs
Publication statusPublished - 2000 Jan 1
Externally publishedYes

Keywords

  • Apoptosis
  • Basic helix-loop-helix (bHLH) transcription factor
  • Hes1
  • Multipotent progenitor cell
  • Neuronal commitment
  • Neurosphere assay

ASJC Scopus subject areas

  • Neuroscience(all)

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  • Cite this

    Nakamura, Y., Sakakibara, S. I., Miyata, T., Ogawa, M., Shimazaki, T., Weiss, S., Kageyama, R., & Okano, H. (2000). The bHLH gene Hes1 as a repressor of the neuronal commitment of CNS stem cells. Journal of Neuroscience, 20(1), 283-293. https://doi.org/10.1523/jneurosci.20-01-00283.2000