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An Optic Nerve Crush Injury Murine Model to Study Retinal Ganglion Cell Survival
Published on: April 25, 2011
Increased neuronal death and disturbed axonal growth in the Polμ-deficient mouse embryonic retina
Jimena Baleriola1, Noemí Álvarez-Lindo1, Pedro de la Villa2
13D Lab (Development, Differentiation and Degeneration), Centro de Investigaciones Biológicas, CSIC, 28040 Madrid, Spain.
Abstract:
Programmed cell death occurs naturally at different stages of neural development, including neurogenesis. The functional role of this early phase of neural cell death, which affects recently differentiated neurons among other cell types, remains undefined. Some mouse models defective in DNA double-strand break (DSB) repair present massive cell death during neural development, occasionally provoking embryonic lethality, while other organs and tissues remain unaffected. This suggests that DSBs occur frequently and selectively in the developing nervous system. We analyzed the embryonic retina of a mouse model deficient in the error-prone DNA polymerase μ (Polμ), a key component of the non-homologous end-joining (NHEJ) repair system. DNA DSBs were increased in the mutant mouse at embryonic day 13.5 (E13.5), as well as the incidence of cell death that affected young neurons, including retinal ganglion cells (RGCs). Polμ(-/-) mice also showed disturbed RGC axonal growth and navigation, and altered distribution of the axonal guidance molecules L1-CAM and Bravo (also known as Nr-CAM). These findings demonstrate that Polμ is necessary for proper retinal development, and support that the generation of DSBs and their repair via the NHEJ pathway are genuine processes involved in neural development.
Insights
DNA double-strand breaks (DSBs) are crucial for neural development. Repairing these breaks using non-homologous end-joining (NHEJ) involving DNA polymerase mu (Polμ) is vital for retinal development and neuron survival.
Area of Science:
- Neuroscience
- Developmental Biology
- Genetics
Background:
- Programmed cell death is essential during neural development, but its role in early neurogenesis remains unclear.
- DNA double-strand breaks (DSBs) and their repair are implicated in neural development, with some repair defects causing embryonic lethality.
Purpose of the Study:
- To investigate the role of DNA polymerase mu (Polμ), a key component of non-homologous end-joining (NHEJ), in embryonic retinal development.
- To determine if DSBs and NHEJ are involved in the programmed cell death of developing neurons.
Main Methods:
- Analysis of a mouse model deficient in DNA polymerase mu (Polμ-/-).
- Assessment of DNA double-strand breaks (DSBs) and cell death incidence in embryonic retinas at E13.5.
- Evaluation of retinal ganglion cell (RGC) axonal growth, navigation, and axonal guidance molecules (L1-CAM, Bravo/Nr-CAM).
Main Results:
- Polμ deficiency led to increased DSBs and heightened cell death in young neurons, including RGCs, in the embryonic retina.
- Mutant mice exhibited impaired RGC axonal growth and navigation.
- Altered distribution of axonal guidance molecules L1-CAM and Bravo (Nr-CAM) was observed in Polμ-/- mice.
Conclusions:
- DNA polymerase mu (Polμ) is essential for proper retinal development.
- The generation of DSBs and their repair via the NHEJ pathway are integral processes in neural development, particularly in the retina.
