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PMID: 10627606 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

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

The Journal of neuroscience : the official journal of the Society for Neuroscience ·Vol. 20 ·No. 1 ·2000-01-01 ·Pages 283-93

Nakamura Y, Sakakibara Si, Miyata T, Ogawa M, Shimazaki T, Weiss S, Kageyama R, Okano H

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 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.

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,cytology Pregnancy Proliferating Cell Nuclear Antigen/analysis Saccharomyces cerevisiae Proteins Stem Cells/chemistry,cytology Transcription, Genetic/physiology
Chemicals
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
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Nakamura Y
Department of Neuroanatomy, Biomedical Research Center, Osaka University, Suita, Osaka 565-0871, Japan.
Sakakibara S i
Miyata T
Ogawa M
Shimazaki T
Weiss S
Kageyama R
Okano H
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Article Info
Journal
The Journal of neuroscience : the official journal of the Society for Neuroscience
Abbr.
J Neurosci
ISSN
1529-2401
Published
2000-01-01
Pages
283-93
Language
English
Region
United States
NLM ID
8102140
PMCID
PMC6774123
Subset
IM
External Links
PubMed source PMC Full Text View journal details
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