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

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

Research output: Contribution to journalArticle

256 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
Publication statusPublished - 2000 Jan 1
Externally publishedYes

Fingerprint

Stem Cells
Neurons
Genes
Brain
Basic Helix-Loop-Helix Transcription Factors
Nestin
Intermediate Filaments
Phenotype
Population

Keywords

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

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Nakamura, Y., Sakakibara, S., Miyata, T., Ogawa, M., Shimazaki, T., Weiss, S., ... 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.

The bHLH gene Hes1 as a repressor of the neuronal commitment of CNS stem cells. / Nakamura, Yuki; Sakakibara, Shinichi; Miyata, Takaki; Ogawa, Masaharu; Shimazaki, Takuya; Weiss, Samuel; Kageyama, Ryoichiro; Okano, Hideyuki.

In: Journal of Neuroscience, Vol. 20, No. 1, 01.01.2000, p. 283-293.

Research output: Contribution to journalArticle

Nakamura, Y, Sakakibara, S, 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, vol. 20, no. 1, pp. 283-293.
Nakamura Y, Sakakibara S, Miyata T, Ogawa M, Shimazaki T, Weiss S et al. The bHLH gene Hes1 as a repressor of the neuronal commitment of CNS stem cells. Journal of Neuroscience. 2000 Jan 1;20(1):283-293.
Nakamura, Yuki ; Sakakibara, Shinichi ; Miyata, Takaki ; Ogawa, Masaharu ; Shimazaki, Takuya ; Weiss, Samuel ; Kageyama, Ryoichiro ; Okano, Hideyuki. / The bHLH gene Hes1 as a repressor of the neuronal commitment of CNS stem cells. In: Journal of Neuroscience. 2000 ; Vol. 20, No. 1. pp. 283-293.
@article{e7483df81fd74f20ada85550511ace01,
title = "The bHLH gene Hes1 as a repressor of the neuronal commitment of CNS stem cells",
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.",
keywords = "Apoptosis, Basic helix-loop-helix (bHLH) transcription factor, Hes1, Multipotent progenitor cell, Neuronal commitment, Neurosphere assay",
author = "Yuki Nakamura and Shinichi Sakakibara and Takaki Miyata and Masaharu Ogawa and Takuya Shimazaki and Samuel Weiss and Ryoichiro Kageyama and Hideyuki Okano",
year = "2000",
month = "1",
day = "1",
language = "English",
volume = "20",
pages = "283--293",
journal = "Journal of Neuroscience",
issn = "0270-6474",
publisher = "Society for Neuroscience",
number = "1",

}

TY - JOUR

T1 - The bHLH gene Hes1 as a repressor of the neuronal commitment of CNS stem cells

AU - Nakamura, Yuki

AU - Sakakibara, Shinichi

AU - Miyata, Takaki

AU - Ogawa, Masaharu

AU - Shimazaki, Takuya

AU - Weiss, Samuel

AU - Kageyama, Ryoichiro

AU - Okano, Hideyuki

PY - 2000/1/1

Y1 - 2000/1/1

N2 - 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.

AB - 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.

KW - Apoptosis

KW - Basic helix-loop-helix (bHLH) transcription factor

KW - Hes1

KW - Multipotent progenitor cell

KW - Neuronal commitment

KW - Neurosphere assay

UR - http://www.scopus.com/inward/record.url?scp=0033993524&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0033993524&partnerID=8YFLogxK

M3 - Article

VL - 20

SP - 283

EP - 293

JO - Journal of Neuroscience

JF - Journal of Neuroscience

SN - 0270-6474

IS - 1

ER -