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A Novel Light Damage Paradigm for Use in Retinal Regeneration Studies in Adult Zebrafish
Published on: October 24, 2013
A Dynamic Change of Microglial States Occurs During the Transition From Photoreceptor Degeneration to Regeneration in
Darshini Ravishankar1, Yuki Takeuchi1, Ichiro Masai1
1Developmental Neurobiology Unit, Okinawa Institute of Science and Technology Graduate University, Okinawa, Japan.
Abstract:
Microglia, brain-resident immune cells, maintain brain homeostasis. However, homeostatic microglia dynamically change into disease-associated microglia in human neurodegenerative diseases. Furthermore, microglia-mediated inflammation is required to initiate neuronal regeneration in zebrafish brain. To understand how functional states of microglia are regulated in response to neuronal degeneration and regeneration, we focused on pde6c mutants, a chronic photoreceptor degeneration zebrafish model. We conducted scRNA-seq analysis on microglia in wild-type sibling and pde6c mutant retinas at the onset of photoreceptor degeneration (5 dpf) and Müller glia-mediated neuronal regeneration (4 wpf). At 5 dpf, retinal microglia consist of three clusters, which correspond to homeostatic, degeneration-response, and stress-response microglia, respectively. The degeneration-response cluster expands in pde6c mutants and expresses genes for neuroprotection and tissue repair. At 4 wpf, retinal microglia comprise four clusters, two of which are specifically produced in pde6c mutants and approach the photoreceptor layer. Furthermore, another cluster is prominently localized in the retinal stem cell niche and shows a transcriptomic profile similar to that of neurogenic-associated microglia (NAM). Comparison of transcriptomic similarity between 4 wpf and 5 dpf microglial clusters revealed that each 4 wpf microglial cluster inherits characteristics of homeostatic, degeneration-response, and stress-response state of 5 dpf microglia in different combinations. Thus, there is a unique heterogeneity of microglia in the initial stage of Müller glia-mediated regeneration. Taken together, our findings reveal a dynamic change of retinal microglia during the transition from photoreceptor degeneration to Müller glia-mediated neuronal regeneration in zebrafish.
Insights
Microglia in zebrafish retinas dynamically shift states during photoreceptor degeneration and regeneration. These brain immune cells exhibit unique heterogeneity, supporting tissue repair and neurogenesis.
Area of Science:
- Neuroscience
- Immunology
- Developmental Biology
Background:
- Microglia, the brain's resident immune cells, are crucial for maintaining brain homeostasis.
- In neurodegenerative diseases, microglia transition from a homeostatic state to disease-associated microglia.
- Microglia-mediated inflammation plays a role in initiating neuronal regeneration in zebrafish.
Purpose of the Study:
- To investigate the dynamic regulation of microglial functional states during neuronal degeneration and regeneration.
- To characterize microglial responses in a zebrafish model of chronic photoreceptor degeneration (pde6c mutants).
Main Methods:
- Single-cell RNA sequencing (scRNA-seq) was performed on microglia from wild-type and pde6c mutant zebrafish retinas.
- Analysis was conducted at two key time points: onset of degeneration (5 days post-fertilization, dpf) and Müller glia-mediated regeneration (4 weeks post-fertilization, wpf).
Main Results:
- At 5 dpf, microglia clustered into homeostatic, degeneration-response, and stress-response states, with the degeneration-response cluster expanding in mutants.
- At 4 wpf, four microglial clusters were identified, including two novel clusters in mutants near the photoreceptor layer.
- A distinct cluster localized to the retinal stem cell niche showed similarity to neurogenic-associated microglia (NAM).
- Microglial clusters at 4 wpf inherited combined characteristics from the 5 dpf states, indicating unique heterogeneity during regeneration.
Conclusions:
- Retinal microglia exhibit dynamic heterogeneity during the transition from photoreceptor degeneration to Müller glia-mediated regeneration.
- These findings reveal distinct microglial states and their roles in neuroprotection, tissue repair, and neurogenesis in zebrafish.
- Understanding these microglial dynamics provides insights into brain repair mechanisms.
