The bHLH gene hes1 as a repressor of the neuronal commitment of CNS stem cells

J Neurosci. 2000 Jan 1;20(1):283-93. doi: 10.1523/JNEUROSCI.20-01-00283.2000.


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 Hes1(-/-) 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / physiology
  • Cell Aggregation
  • Cell Differentiation / physiology
  • Cell Lineage / physiology
  • Cells, Cultured
  • Female
  • Fungal Proteins / genetics*
  • Helix-Loop-Helix Motifs / physiology*
  • In Situ Nick-End Labeling
  • Intermediate Filament Proteins / analysis
  • Mice
  • Mice, Knockout
  • Microtubule-Associated Proteins / analysis
  • Nerve Tissue Proteins*
  • Nestin
  • Neurofilament Proteins / analysis
  • Neurons / chemistry
  • Neurons / cytology*
  • Pregnancy
  • Proliferating Cell Nuclear Antigen / analysis
  • Saccharomyces cerevisiae Proteins*
  • Stem Cells / chemistry
  • Stem Cells / cytology*
  • Transcription, Genetic / physiology


  • Fungal Proteins
  • HES1 protein, S cerevisiae
  • Intermediate Filament Proteins
  • Microtubule-Associated Proteins
  • Nerve Tissue Proteins
  • Nes protein, mouse
  • Nestin
  • Neurofilament Proteins
  • Proliferating Cell Nuclear Antigen
  • Saccharomyces cerevisiae Proteins
  • neurofilament protein M