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Cited by 74Neurogenesis and neuroplasticity mechanismsCancer-related Molecular PathwaysDevelopmental Biology and Gene Regulation

Neural Precursor Cells Differentiating in the Absence of Rb Exhibit Delayed Terminal Mitosis and Deregulated E2F 1 and 3 Activity

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Callaghan, Debbie A., Dong, Li, Callaghan, Steven M., Hou, Yang Xun, Dagnino, Lina, Slack, Ruth S.·1999·Developmental Biology
DOI 10.1006/dbio.1998.9162
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Abstract

The severe neurological deficit in embryos carrying null mutations for the retinoblastoma (Rb) gene suggests that Rb plays a crucial role in neurogenesis. While developing neurons undergo apoptosis in vivo neural precursor cells cultured from Rb-deficient embryos appear to differentiate and survive. To determine whether Rb is an essential regulator of the intrinsic pathway modulating terminal mitosis we examined the terminal differentiation of primary cortical progenitor cells and bFGF-dependent neural stem cells derived from Rb-deficient mice. Although Rb -/- neural precursor cells are able to differentiate in vitro we show that these cells exhibit a significant delay in terminal mitosis relative to wild-type cells. Furthermore, Rb -/- cells surviving in vitro exhibit an upregulation of p107 that is found in complexes with E2F3. This suggests that p107 may partially compensate for the loss of Rb in neural precursor cells. Functional ablation of Rb family proteins by adenovirus-mediated delivery of an E1A N-terminal mutant results in apoptosis in Rb-deficient cells, consistent with the interpretation that other Rb family proteins may facilitate differentiation and survival. While p107 is upregulated and interacts with the putative Rb target E2F3 in neural precursor cells, our results indicate that it clearly cannot restore normal E2F regulation. Rb-deficient cells exhibit a significant enhancement of E2F 1 and 3 activity throughout differentiation concomitant with the aberrant expression of E2F-inducible genes. In these studies we show that Rb is essential for the regulation of E2F 1 and 3 activity as well as the onset of terminal mitosis in neural precursor cells.

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  • In the brain, RB levels increase as progenitor cells undergo cell cycle exit, and loss of Rb delays cell cycle exit.

    “In the brain, RB levels increase as progenitor cells normally undergo cell cycle exit and loss of Rb results in delayed cell cycle exit in these cells44,49,53,54.”

    From Cellular mechanisms of tumour suppression by the retinoblastoma gene (2008) · cites this paper as [53]

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Research works printed but not linked: 2

  1. Gloster, A., El-Bizri, H., Bamji, S. X., Rogers, D., and Miller, F. D. Early induction of T␣1 ␣-tubulin transcription in neurons of the developing nervous system. J. Comp. Neurol., in press.
  2. Wu, X., and Levine, A. J. (1994). p53 and E2F1 cooperate to mediate apoptosis. Proc. Natl. Acad. Sci. USA 91, 3602-3606.

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Authors
Callaghan, D. A., Dong, L., Callaghan, S. M., Hou, Y. X., Dagnino, L., & Slack, R. S.
Affiliations
University of Ottawa (CA)
Corresponding author
Slack, Ruth S.
ORCID
Venue
Developmental Biology
Publisher
Elsevier BV
Published
1999-03
Volume
207
Issue
2
Pages
257-270
ISSN
0012-1606 (ISSN-L)
DOI
10.1006/dbio.1998.9162
OpenAlex
W1986249155
Cited by
74
References
39
Citations by year
2025: 1 · 2022: 1 · 2021: 1 · 2020: 2 · 2019: 2 · 2018: 1 · 2016: 1 · 2013: 2 · 2012: 3
FWCI
1.70
Type
journal article
Language
en
Open access
Licence
Locations
  • Developmental Biology (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Medical Research Council Canada
  • Medical Research Council
Topics
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
  • Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
Keywords
retinoblastoma protein, neural progenitor cells, E2F1, E2F3, p107, neural stem cells, cortical progenitor cells, neuronal differentiation, apoptosis, neurogenesis
MeSH terms
Adenoviridae, Animals, Carrier Proteins, Cell Differentiation, Cells, Cultured, DNA-Binding Proteins, Immunohistochemistry, Mitosis, Neurons, Nuclear Proteins, Protein Binding, Stem Cells, Transcription Factors, Retinoblastoma Protein, Fibroblast Growth Factor 2, Apoptosis, Mice, Knockout, Gene Expression Regulation, Developmental, Cell Cycle Proteins, Transcription Factor DP1, E2F Transcription Factors, E2F1 Transcription Factor, E2F3 Transcription Factor, Retinoblastoma-Like Protein p107, Mice, Retinoblastoma-Binding Protein 1

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