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RNA Binding Motif 5 Gene Deletion Modulates Cell Signaling in a Sex-Dependent Manner but Not Hippocampal Cell Death
Jeffrey Farooq1,2, Kara Snyder1,2, Keri Janesko-Feldman3
1USF Health Heart Institute, University of South Florida, Morsani College of Medicine, Tampa, Florida, USA.
Abstract:
RNA-binding motif 5 (RBM5) is a pro-death tumor suppressor gene in cancer cells. It remains to be determined if it is neurotoxic in the brain or rather if it plays a fundamentally different role in the central nervous system (CNS). Brain-specific RBM5 knockout (KO) mice were given a controlled cortical impact (CCI) traumatic brain injury (TBI). Markers of acute cellular damage and repair were measured in hippocampal homogenates 48 h post-CCI. Hippocampal CA1/CA3 cell counts were assessed 7 days post-CCI to determine if early changes in injury markers were associated with histological outcome. No genotype-dependent differences were found in the levels of apoptotic markers (caspase 3, caspase 6, and caspase 9). However, KO females had a paradoxical increase in markers of pro-death calpain activation (145/150-spectrin and breakdown products [SBDP]) and in DNA repair/survival markers. (pH2A.x and pCREB). CCI-injured male KOs had a significant increase in phosphorylated calcium/calmodulin-dependent protein kinase II (pCaMKII). Despite sex/genotype-dependent differences in KOs in the levels of acute cell signaling targets involved in cell death pathways, 7 day hippocampal neuronal survival did not differ from that of wild types (WTs). Similarly, no differences in astrogliosis were observed. Finally, gene analysis revealed increased estrogen receptor α (ERα) levels in the KO hippocampus in females and may suggest a novel mechanism to explain sex-dimorphic effects on cell signaling. In summary, RBM5 inhibition did not affect hippocampal survival after a TBI in vivo but did modify targets involved in neural signal transduction/Ca2+ signaling pathways. Findings here support the view that RBM5 may serve a purpose in the CNS that is dissimilar from its traditional pro-death role in cancer.
Insights
RNA-binding motif 5 (RBM5) gene knockout did not impact survival after traumatic brain injury (TBI) in mice. However, RBM5 inhibition altered neural signaling pathways, suggesting a different role in the central nervous system (CNS).
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- RNA-binding motif 5 (RBM5) is a known tumor suppressor gene in cancer cells.
- Its role in the central nervous system (CNS) and potential neurotoxicity remain uncharacterized.
- Investigating RBM5's function in the brain is crucial for understanding its broader biological significance.
Purpose of the Study:
- To determine the neurotoxic effects of RBM5 in the brain following traumatic brain injury (TBI).
- To investigate the role of RBM5 in cellular damage and repair mechanisms in the hippocampus post-TBI.
- To explore potential sex-dependent differences in RBM5's response to TBI.
Main Methods:
- Brain-specific RBM5 knockout (KO) mice were subjected to controlled cortical impact (CCI) to induce TBI.
- Apoptotic markers, calpain activation, and DNA repair/survival markers were quantified in hippocampal homogenates.
- Neuronal survival and astrogliosis were assessed histologically 7 days post-CCI.
- Gene expression analysis, including estrogen receptor alpha (ERα), was performed.
Main Results:
- No significant differences in apoptotic markers (caspase 3, 6, 9) were observed between RBM5 KO and wild-type (WT) mice.
- Female KO mice showed increased markers of calpain activation and DNA repair/survival pathways.
- Male KO mice exhibited increased phosphorylated CaMKII.
- Despite altered signaling pathways, hippocampal neuronal survival and astrogliosis were not different between genotypes 7 days post-TBI.
- Female KO mice displayed elevated estrogen receptor α (ERα) levels.
Conclusions:
- RBM5 inhibition does not impair hippocampal neuronal survival following TBI in vivo.
- RBM5 knockout modifies specific neural signaling pathways, including Ca2+ signaling, in a sex-dependent manner.
- These findings suggest RBM5 has a distinct role in the CNS compared to its pro-death function in cancer.
- Estrogen receptor α may play a role in the sex-dimorphic effects observed in RBM5 KO mice.
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