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Subspecialties Basic & Translational Research, Retina, Retina

Turning Back Time

The Neural Retina Leucine Zipper gene (Nrl) plays a fascinating role in retinal development. It encodes a transcription factor that acts as a master control switch for rod photoreceptor differentiation by regulating the expression of important rod-specific genes. These include the rhodopsin-encoding RHO, and PDE6B – a subunit of the cGMP-PDE protein complex, which is essential to light-mediated neurotransmission in the retina. The interplay between the various developmental morphogens and signaling cascades is nuanced and complex… What you really need to know is that all photoreceptor precursor cells develop into cones in the absence of Nrl. But what’s really interesting about Nrl? Its action is reversible. Inactivate it, and rods become reprogrammed and turn into cones.

We’ve known for many years that retinitis pigmentosa (RP) is caused by mutations in genes that are expressed in rods, not cones, and it results in a progressive sequence of rod cell death followed by cone loss. Rod degeneration results in the collapse of the outer nuclear layer (ONL) of the retina, and this generates an oxidative, nutrient-deficient environment that is toxic to cones. It’s actually the cone loss that’s the most debilitating. Think about it: rods are absent from the all-cone fovea centralis, and it’s hard to find an environment where rod-mediated vision is actually used – particularly in urban settings, where artificial light is endemic and most bedside tables have a lamp.

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About the Author

Kang Zhang

Zhang is Professor of Ophthalmology and Chief of Ophthalmic Genetics at the University of California San Diego, CA, USA. His clinical and research focuses are on novel disease gene targets and treatment, gene and stem cell-based therapies in AMD, diabetic retinopathy, and inherited retinal degeneration. His laboratory uses genetic analyses to gain insights into the molecular mechanisms that underpin macular degeneration and other eye diseases; this knowledge is then used to make genetic changes that either protect the retina from damage, or actively encourage regeneration. Zhang was voted to the 2018 Power List.

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