Caspase 3 Deficiency Rescues Peripheral Nervous System Defect in Retinoblastoma Nullizygous Mice
Open accessAbstract
The retinoblastoma tumor suppressor protein, pRb, is a key regulator of cell cycle and has been implicated in the terminal differentiation of neuronal cells. Mice nullizygous for pRb die by embryonic day 14.5 from hematopoietic and neurological defects attributed to failed differentiation (Clarke et al., 1992; Jacks et al., 1992; Lee et al., 1992). Previous studies by MacLeod et al. (1996) have demonstrated that the loss of p53 protects Rb-deficient CNS neurons but not peripheral nervous system (PNS) neurons from cell death. Thus, the mechanisms by which PNS neurons undergo apoptosis in response to Rb deficiency remain unknown. In view of the pivotal role of caspase 3 in the regulation of neuronal apoptosis during development, we examined its function in the execution of the wide-spread neuronal cell death induced by Rb deficiency. Our results support a number of conclusions. First, we show that caspase 3 becomes activated in all neuronal populations undergoing apoptosis. Second, caspase 3 deficiency does not extend the life span of Rb null embryos, because double null mutants exhibit high rates of liver apoptosis resulting in erythropoietic failure. Third, Rb/caspase 3 double-mutant neurons of the CNS exhibit widespread apoptosis similar to that seen in Rb mutants alone; thus caspase 3 deficiency does not protect this population from apoptosis. Finally, in contrast to the CNS, neurons of the PNS including those comprising the trigeminal ganglia and the dorsal root ganglia are protected from apoptosis in Rb/caspase 3 double-mutant embryos. Examination of the mechanistic differences between these two cell types suggest that CNS neurons may invoke other caspases to facilitate apoptosis in the absence of caspase 3. These findings suggest that PNS neurons are dependent on caspase 3 for the execution of apoptosis and that caspase 3 may serve as a key therapeutic target for neuroprotection after injury of this cell type.
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Abnormal proliferation induced by loss of RB is often accompanied by increased cell death through p53-dependent and independent mechanisms.
“abnormal proliferation that is induced by loss of RB is often accompanied by increased cell death, through p53-dependent and independent mechanisms49,57,87–91.”
From Cellular mechanisms of tumour suppression by the retinoblastoma gene (2008) · cites this paper as [91]
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- Authors
- Simpson, M. T. W., MacLaurin, J. G., Xu, D., Ferguson, K. L., Vanderluit, J. L., Davoli, M. A., Roy, S., Nicholson, D. W., Robertson, G. S., Park, D. S., & Slack, R. S.
- Affiliations
- University of Ottawa (CA)
- Merck Canada Inc. (Canada) (CA)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2001-09-15
- Volume
- 21
- Issue
- 18
- Pages
- 7089-7098
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6762980
- OpenAlex
- W2157122927
- Cited by
- 35
- References
- 36
- Citations by year
- 2018: 1 · 2016: 1 · 2013: 2 · 2012: 2
- FWCI
- 1.40
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Wellcome Trust
- Canadian Stroke Network
- Canadian Institutes of Health Research
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
- Keywords
- caspase-3, retinoblastoma protein, peripheral nervous system neurons, neuronal apoptosis, central nervous system neurons, trigeminal ganglion, dorsal root ganglia, neuroprotection, p53
- MeSH terms
- Animals, Central Nervous System, Crosses, Genetic, Enzyme Induction, Fluorescent Dyes, Ganglia, Spinal, Genotype, Neurons, Organ Specificity, Retinoblastoma Protein, Amyloid beta-Protein Precursor, Apoptosis, Peripheral Nervous System, Mice, Knockout, Gene Expression Regulation, Developmental, Caspases, In Situ Nick-End Labeling, Mice, Caspase 3
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