Insights into eyesight – discovery of retina regulatory molecules



Published 6th September 2018

15 novel genes related to retinal function have been found in research published by Dr. Melanie Samuel and colleagues in Cell Reports. The research reveals previously unknown retinal regulators which will help expand our understanding of the genetic landscape that regulates retinal function and uncover how genes are involved in vision loss and disease.

The retina processes visual information from the world around us and relays it to the brain. This sensory circuit is complex but highly ordered. It is comprised of distinct neural layers, and each layer has an array of different neuron types. These neurons are supported by a rich vascular system.

Vision defects globally affect around 253 million people. Such diseases can arise from disruptions to different parts of the visual circuit. For example, vascular changes can be a sign of diabetic neuropathy and defects in light-sensing photoreceptors can lead to retinitis pigmentosa. Yet many of the genes and mechanisms responsible for vision loss remain unknown.

This schematic outlines the complex circuitry in the retina. Each layer contains different neuron types that synapse onto the layer below, from the top layer that detects light to the bottom layer where axons transmit visual information to the brain.

In this research, Dr. Samuel and colleagues selected a sub-set of animal lines from the IMPC in which individual genes had been modified to eliminate their function. They then developed a specialized pipeline of high-throughput retinal screening to examine the role of these genes in more detail. The criteria for selecting candidate genes included those with human orthologues and those with expression in the retina or brain.

The availability of broad based and comprehensive phenotyping data from the IMPC helped researchers focus their search for genes relating to the retina.

In-depth analysis included examining gene expression, synapse organisation, cell morphology and the patterning of blood vessels.

Of the 102 mutant lines analysed, 16 genes were identified that regulated retinal function, 15 of these were novel and not previously associated with retina function.

A range of diverse observations were seen. Lines were found with altered vessel density and branching, disrupted synaptic organisation and neuron loss.

Here, analysis of blood vessels in the retina shows abnormalities including decreased vessel number (Rnf10) and tortuosity (Adsl) in comparison to the wild type image on the left hand side.

Here, analysis of blood vessels in the retina shows abnormalities including decreased vessel number (Rnf10) and tortuosity (Adsl) in comparison to the wild type image on the left hand side.

Many of the genes displayed a wide range of cellular functions and may also be important elsewhere in the body. Data available through the IMPC database supported this, as many of the lines had additional phenotypes, including body composition and central nervous system regulation deficits (suggested by altered body composition and open field tests, respectively).

“The results from the study highlight the kind of discoveries that are possible through harnessing the remarkable data and resources available from the IMPC.  With these efforts, we hope to continue to map the compendium of genes that regulate the retina and the brain so that we can make progress in treating human neural diseases,” said corresponding author, Dr. Samuel, assistant professor of neuroscience and the Huffington Center on Aging at Baylor College of Medicine.

To read the research click here

Interested in learning more? Dr. Samuel recently told us about her lab’s research in the video ‘What makes us unique? Exploring the role of genetics and neural function’

Other contributors to this work include Nicholas E. Albrecht, Jonathan Alevy, Danye Jiang, Courtney A. Burger, Brian I. Liu, Fenge Li, Julia Wang, Seon-Young Kim, Chih-Wei Hsu, Sowmya Kalaga, Uchechukwu Udensi, Chinwe Asomugha, Ritu Bohat, Angelina Gaspero, Mónica J. Justice, Peter D. Westenskow, Shinya Yamamoto and John R. Seavitt. The authors are affiliated with one or more of the following institutions: Baylor College of Medicine, Texas Children’s Hospital, and the Hospital for Sick Children, Toronto.


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Calcium-ATPases convey calcium ions (Ca2+) from the cytoplasm to the extracellular space via active transport (using ATP as an energy source), and thus fundamentally contribute to the control of a wide variety of Ca2+-dependent processes in virtually any type of cell in humans and animals. Scientists in the group of Dr. Uwe Schulte and Prof. Dr. Bernd Fakler at the Institute of Physiology at the University of Freiburg have successfully unraveled the molecular appearance of this well-known ‘ion pump’: Different from classical textbook knowledge, Ca2+-pumps of the plasma membrane (PMCAs) are identified as protein complexes that are assembled from two ATP-hydrolyzing transporter proteins and two as yet unknown subunits, Neuroplastin and Basigin. These two novel protein subunits are essential for stability and trafficking of the PMCA complexes to the plasma membrane and control the PMCA-mediated Ca2+-transport. The researchers have presented their work in the current issue of the scientific journal Neuron.

A variety of cellular processes such as release of transmitters and hormones, regulation of enzymatic activities and excitability, contraction or cell motility are controlled by intracellular Ca2+. These processes are switched on by Ca2+-influx, mostly through Ca2+-permeable ion channels, and they are switched off by Ca2+-ATPases in the plasma membrane, the PMCAs. The Fakler group has now shown that this switch-off by PMCAs may only take a few ten milliseconds, in contrast to the seconds-lasting periods assumed previously. As the mechanism behind this unexpectedly high efficiency in Ca2+-transport activity, the researchers identified co-assembly of the ATPase subunits with the auxiliary proteins Neuroplastin and Basigin which promote effective integration of the PMCA complexes into the plasma membrane. Deletion of both Neuroplastin and Basigin in CNS neurons leads to severe disturbance of neuron signal transduction and ultimately to cell death.

Even before their identification as auxiliary subunits of PMCA complexes, Neuroplastin and Basigin have not been ‘unknowns’. In fact, investigations by several groups predominantly on knock-out animals and tissues demonstrated fundamental involvement of both proteins in quite a variety of different cellular processes ranging from formation, operation and plasticity of synapses in central neurons, to spermatogenesis and fertilization, or infection of erythrocytes by plasmodium, the pathogen of malaria. So far, however, the molecular mechanisms underlying these processes have remained unresolved. Based on the newly established results by the Freiburg scientists, it appears reasonable to assume that all the aforementioned processes share a common mechanism – the PMCA-mediated control of intracellular Ca2+-signaling.


Research article: Neuroplastin and Basigin Are Essential Auxiliary Subunits of Plasma Membrane Ca2+-ATPases and Key Regulators of Ca2+ Clearance



Published 16th April 2018

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