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Retinal Detachment Model in Rodents by Subretinal Injection of Sodium Hyaluronate
Published on: September 11, 2013
Mammalian STE20-like kinase 2, not kinase 1, mediates photoreceptor cell death during retinal detachment
H Matsumoto1, Y Murakami1, K Kataoka1
1Retina Service, Angiogenesis Laboratory, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA.
Abstract:
Photoreceptor cell death is the definitive cause of vision loss in retinal detachment (RD). Mammalian STE20-like kinase (MST) is a master regulator of both cell death and proliferation and a critical factor in development and tumorigenesis. However, to date the role of MST in neurodegeneration has not been fully explored. Utilizing MST1(-/-) and MST2(-/-) mice we identified MST2, but not MST1, as a regulator of photoreceptor cell death in a mouse model of RD. MST2(-/-) mice demonstrated significantly decreased photoreceptor cell death and outer nuclear layer (ONL) thinning after RD. Additionally, caspase-3 activation was attenuated in MST2(-/-) mice compared to control mice after RD. The transcription of p53 upregulated modulator of apoptosis (PUMA) and Fas was also reduced in MST2(-/-) mice post-RD. Retinas of MST2(-/-) mice displayed suppressed nuclear relocalization of phosphorylated YAP after RD. Consistent with the reduction of photoreceptor cell death, MST2(-/-) mice showed decreased levels of proinflammatory cytokines such as monocyte chemoattractant protein 1 and interleukin 6 as well as attenuated inflammatory CD11b cell infiltration during the early phase of RD. These results identify MST2, not MST1, as a critical regulator of caspase-mediated photoreceptor cell death in the detached retina and indicate its potential as a future neuroprotection target.
Insights
Mammalian STE20-like kinase 2 (MST2) deficiency protects photoreceptor cells from death in retinal detachment (RD). This finding suggests MST2 as a potential target for neuroprotection strategies against vision loss.
Area of Science:
- Ophthalmology
- Neuroscience
- Cell Biology
Background:
- Photoreceptor cell death causes vision loss in retinal detachment (RD).
- Mammalian STE20-like kinase (MST) regulates cell death and proliferation, but its role in neurodegeneration is underexplored.
- MST comprises MST1 and MST2 isoforms, with distinct biological functions.
Purpose of the Study:
- To investigate the specific roles of MST1 and MST2 in photoreceptor cell death following retinal detachment.
- To determine if MST2 acts as a regulator of neurodegeneration in a mouse model of RD.
Main Methods:
- Utilized MST1(-/-) and MST2(-/-) knockout mice in a mouse model of retinal detachment.
- Assessed photoreceptor cell death, outer nuclear layer (ONL) thickness, and caspase-3 activation post-RD.
- Quantified the transcription of apoptosis-related genes (PUMA, Fas) and inflammatory cytokines (MCP-1, IL-6).
- Analyzed YAP nuclear relocalization and CD11b cell infiltration.
Main Results:
- MST2 deficiency, but not MST1 deficiency, significantly reduced photoreceptor cell death and ONL thinning in RD mice.
- Caspase-3 activation, PUMA, and Fas transcription were attenuated in MST2(-/-) mice post-RD.
- MST2(-/-) retinas showed suppressed YAP nuclear relocalization and reduced levels of proinflammatory cytokines and inflammatory cell infiltration.
- Reduced photoreceptor death correlated with decreased inflammation in MST2(-/-) mice.
Conclusions:
- MST2, not MST1, is a critical regulator of caspase-mediated photoreceptor cell death in the detached retina.
- MST2 plays a significant role in the inflammatory response during early retinal detachment.
- Targeting MST2 may offer a novel neuroprotective strategy for vision loss associated with retinal detachment.
