The Role of Retinoblastoma Protein in Dorsal Root Ganglion Neurons and Its Implications on Chemotherapy Induced Peripheral Neuropathy

Date
2022
Authors
Herrera, Bianca
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Abstract

Chemotherapy Induced Peripheral Neuropathy (CIPN) is a consequence of cancer treatments that include chemotherapeutic agents such as platinum-based compounds. While the mechanisms of CIPN are still unclear, evidence suggests that neurotoxic damage to dorsal root ganglion (DRG) sensory neurons is likely a primary mechanism. It has been shown that these therapeutic compounds induce cell cycle re-entry and cell death in DRG and is well known that cell cycle activity in neurons is highly induced in various neurodegenerative disorders. This supports a hypothesis that cell cycle re-entry mediated neurotoxicity in DRG is the underlying molecular mechanism for CIPN. To test this hypothesis, a novel transgenic mouse model (PirtRB) was established using the phosphoinositide interacting regulator of TRP (Pirt) promoter driven Cre mouse line in DRG to ablate retinoblastoma protein gene (Rb) by cross-breeding with the Rb-floxed mouse line. Rb protein, a key cell cycle regulator, prevents G1/S phase transition by binding to E2F family proteins. In PirtRB mice, the ablation of Rb in DRG induced neuronal cell loss, supporting the critical role of Rb for viability of DRG neurons. Consistently, PirtRB mice also exhibited increased mechanical allodynia, a CIPN-like neuropathic condition which supports the inactivation of Rb and subsequent cell cycle re-entry as a key molecular mechanism of the development of CIPN. Collectively, these data strongly support our hypothesis that aberrant cell cycle re-entry in DRG causes neurodegeneration and modulation of Rb-mediated cell signaling process may provide an effective therapeutic target for the treatment of CIPN.

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Keywords
Cell Cycle, Chemotherapy, DRG, Neurodegeneration, Peripheral Neuropathy, Retinoblastoma
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Department
Neuroscience, Developmental and Regenerative Biology