Identification of genes that restrict astrocyte differentiation of midgestational neural precursor cells

T. Sanosaka, M. Namihira, H. Asano, J. Kohyama, K. Aisaki, K. Igarashi, J. Kanno, Kinichi Nakashima

Research output: Contribution to journalArticle

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Abstract

During development of the mammalian CNS, neurons and glial cells (astrocytes and oligodendrocytes) are generated from common neural precursor cells (NPCs). However, neurogenesis precedes gliogenesis, which normally commences at later stages of fetal telencephalic development. Astrocyte differentiation of mouse NPCs at embryonic day (E) 14.5 (relatively late gestation) is induced by activation of the transcription factor signal transducer and activator of transcription (STAT) 3, whereas at E11.5 (mid-gestation) NPCs do not differentiate into astrocytes even when stimulated by STAT3-activating cytokines such as leukemia inhibitory factor (LIF). This can be explained in part by the fact that astrocyte-specific gene promoters are highly methylated in NPCs at E11.5, but other mechanisms are also likely to play a role. We therefore sought to identify genes involved in the inhibition of astrocyte differentiation of NPCs at midgestation. We first examined gene expression profiles in E11.5 and E14.5 NPCs, using Affymetrix GeneChip analysis, applying the Percellome method to normalize gene expression level. We then conducted in situ hybridization analysis for selected genes found to be highly expressed in NPCs at midgestation. Among these genes, we found that N-myc and high mobility group AT-hook 2 (Hmga2) were highly expressed in the E11.5 but not the E14.5 ventricular zone of mouse brain, where NPCs reside. Transduction of N-myc and Hmga2 by retroviruses into E14.5 NPCs, which normally differentiate into astrocytes in response to LIF, resulted in suppression of astrocyte differentiation. However, sustained expression of N-myc and Hmga2 in E11.5 NPCs failed to maintain the hypermethylated status of an astrocyte-specific gene promoter. Taken together, our data suggest that astrocyte differentiation of NPCs is regulated not only by DNA methylation but also by genes whose expression is controlled spatio-temporally during brain development.

Original languageEnglish
Pages (from-to)780-788
Number of pages9
JournalNeuroscience
Volume155
Issue number3
DOIs
Publication statusPublished - Aug 26 2008
Externally publishedYes

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Astrocytes
Genes
AT-Hook Motifs
Leukemia Inhibitory Factor
Gene Expression
STAT3 Transcription Factor
Pregnancy
Telencephalon
myc Genes
Neurogenesis
Oligodendroglia
Brain
DNA Methylation
Retroviridae
Fetal Development
Transcriptome
Neuroglia
In Situ Hybridization
Transcription Factors
Cytokines

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

Cite this

Identification of genes that restrict astrocyte differentiation of midgestational neural precursor cells. / Sanosaka, T.; Namihira, M.; Asano, H.; Kohyama, J.; Aisaki, K.; Igarashi, K.; Kanno, J.; Nakashima, Kinichi.

In: Neuroscience, Vol. 155, No. 3, 26.08.2008, p. 780-788.

Research output: Contribution to journalArticle

Sanosaka, T, Namihira, M, Asano, H, Kohyama, J, Aisaki, K, Igarashi, K, Kanno, J & Nakashima, K 2008, 'Identification of genes that restrict astrocyte differentiation of midgestational neural precursor cells', Neuroscience, vol. 155, no. 3, pp. 780-788. https://doi.org/10.1016/j.neuroscience.2008.06.039
Sanosaka, T. ; Namihira, M. ; Asano, H. ; Kohyama, J. ; Aisaki, K. ; Igarashi, K. ; Kanno, J. ; Nakashima, Kinichi. / Identification of genes that restrict astrocyte differentiation of midgestational neural precursor cells. In: Neuroscience. 2008 ; Vol. 155, No. 3. pp. 780-788.
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