Prominent regulators of neurogenesis are also critical in maintaining eye health

A group of researchers at Scintillon Institute in San Diego, California and their collaborators identified important roles of myocyte enhancer factor 2 (MEF2) in the pathogenesis of stress-induced photoreceptor degeneration, a condition that is thought to contribute to eye diseases, such as retinitis pigmentosa and age-related macular degeneration, as described in two recent publications (1,2). MEF2 is an activity-dependent transcription factor which is expressed in various organs, such as the heart, lymphocytes and brain. Dr. Stuart Lipton’s group has continuously worked on MEF2 since 1993, when they first isolated MEF2C, one of four mammalian MEF2 isoforms, in the developing brain. These researchers made seminal discoveries that established the notion that MEF2 transcription factors are prominent regulators of neurogenesis and neuronal survival in the brain. More recently, their work on MEF2C mutant mice led to the recognition of the human disease called MEF2C haploinsufficiency syndrome, in which children with heterozygous loss-of-function MEF2C mutations suffer from severe neurological conditions, including autism spectrum disorders, developmental and intellectual disabilities and seizures.

Scientists at the Neural Center of the Scintillon Institute have been expanding on MEF2 research, most recently turning their eyes to eye diseases (pun intended). Retinal photoreceptor cells express two MEF2 isoforms: MEF2C and MEF2D, the latter apparently being the predominant form. In a recent study, the researchers examined mutant mice completely lacking MEF2C or MEF2D (MEF2C- or MEF2D- “null” mice). Interestingly, both mutant mice developed drastic retinal degenerations by postnatal day 30. They then took a candidate approach to identify the molecular pathways affected by the loss of MEF2D in MEF2D-null mice. Among the pathways they examined was the PGC1? pathway, which regulates mitochondrial biogenesis and thereby protects cells from degeneration. The Lipton group determined that transcription of PGC1? was indeed reduced in MEF2D-null mice. Yet by overexpressing PGC1? in the retina of MEF2D-null mice, the researchers found that the retinal degeneration could be rescued.

In another related study, they examined mice lacking one copy of MEF2D (MEF2D-heteretozygous or “het” mice). Unlike MEF2D-null mice, MEF2D-het mice did not show any retinal regeneration when they were raised under normal housing environment. The researchers then exposed MEF2D-het mice to a strong white fluorescent light for 2 hours. While this light exposure did not induce any retinal degeneration in the wild-type mice, it did cause significant retinal cell death in MEF2D-het mice. The light exposure massively produced reactive oxygen species (ROS), which appeared to be the toxic cause. When searching for affected downstream pathways, they found that the transcription factor NRF2, a regulator of the cellular antioxidant defense response, fails to be induced by light exposure in MEF2D mutant mice. The researchers attempted to reverse light-induced retinal cell death by treating the MEF2D-het mice with carnosic acid, a chemical they had previously identified as a potent antioxidant and NRF2 activator. Intriguingly, treatment of carnosic acid drastically ameliorated the amount of light-induced retinal cell death in the mutant mice.

Together, these studies from the Scintillon Institute identify MEF2 transcription factors as crucial molecules in maintaining eye health. Importantly, they have shown that MEF2 and its downstream pathways can be targeted by drugs such as carnosic acid. Incidentally, carnosic acid is a naturally occurring chemical that is contained in herbs such as rosemary and sage. So, there may be a health benefit in cooking chicken and turkey with rosemary!

1. Proc Natl Acad Sci USA 114, E4048

2. Inv Opthal Vis Sci 58, 3741

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Tuesday, August 8th, 2017 State of Research

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