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Published on: November 19, 2011
Forward genetic screening using fundus spot scale identifies an essential role for Lipe in murine retinal homeostasis
Seher Yuksel1, Bogale Aredo1, Yeshumenesh Zegeye1
1Department of Ophthalmology, UT Southwestern Medical Center, Dallas, TX, USA.
Abstract:
Microglia play a role in the pathogenesis of many retinal diseases. Fundus spots in mice often correlate with the accumulation of activated subretinal microglia. Here we use a semiquantitative fundus spot scoring scale in combination with an unbiased, state-of-the-science forward genetics pipeline to identify causative associations between chemically induced mutations and fundus spot phenotypes. Among several associations, we focus on a missense mutation in Lipe linked to an increase in yellow fundus spots in C57BL/6J mice. Lipe-/- mice generated using CRISPR-Cas9 technology are found to develop accumulation of subretinal microglia, a retinal degeneration with decreased visual function, and an abnormal retinal lipid profile. We establish an indispensable role of Lipe in retinal/RPE lipid homeostasis and retinal health. Further studies using this new model will be aimed at determining how lipid dysregulation results in the activation of subretinal microglia and whether these microglia also play a role in the subsequent retinal degeneration.
Insights
Lipid metabolism is crucial for retinal health. A mutation in Lipe causes lipid imbalance, leading to microglial activation and retinal degeneration in mice, highlighting Lipe's vital role.
Area of Science:
- Ophthalmology
- Neuroscience
- Genetics
Background:
- Microglia are implicated in retinal disease pathogenesis.
- Fundus spots in mice are linked to activated subretinal microglia accumulation.
Purpose of the Study:
- To identify genetic mutations causing fundus spot phenotypes using forward genetics.
- To investigate the role of the Lipe gene in retinal health and lipid homeostasis.
Main Methods:
- Utilized a semiquantitative fundus spot scoring scale.
- Employed a forward genetics pipeline to screen chemically induced mutations.
- Generated Lipe knockout (Lipe-/-) mice using CRISPR-Cas9 technology.
Main Results:
- Identified a missense mutation in Lipe associated with increased yellow fundus spots in mice.
- Lipe-/- mice exhibited subretinal microglia accumulation, retinal degeneration, vision impairment, and altered retinal lipid profiles.
- Established Lipe's essential role in maintaining retinal and retinal pigment epithelium (RPE) lipid homeostasis.
Conclusions:
- Lipe is indispensable for retinal lipid homeostasis and overall retinal health.
- Further research will explore the link between lipid dysregulation, microglial activation, and retinal degeneration.
