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The Journal of Neuroscience, January 1, 2000, 20(1):283-293

The bHLH Gene Hes1 as a Repressor of the Neuronal Commitment of CNS Stem Cells

Yuki Nakamura¹, Shin-ichi Sakakibara^{1, 2}, Takaki Miyata¹, Masaharu Ogawa³, Takuya Shimazaki⁵, Samuel Weiss⁵, Ryoichiro Kageyama⁴, and Hideyuki Okano^{1, 2}

¹ Department of Neuroanatomy, Biomedical Research Center, Osaka University, Suita, Osaka 565-0871, Japan, ² Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, Minato, Tokyo 105-0011, Japan, ³ Laboratory for Cell Culture Development, Brain Science Institute, The Institute of Physical and Chemical Research, Wako, Saitama 351-0198, Japan, ⁴ Institute for Virus Research, Kyoto University, Kyoto 606-8507, Japan, and ⁵ Genes and Development Research Group, University of Calgary Faculty of Medicine, Calgary, Alberta T2N 4N1, Canada

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.

Key words: Hes1; basic helix-loop-helix (bHLH) transcription factor; neuronal commitment; multipotent progenitor cell; neurosphere assay; apoptosis

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Copyright © 2000 Society for Neuroscience  0270-6474/0/201283-11$05.00/0

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