Investigating the mysteries of unconscious vision

12 June 2020

As you read this article, a cascade of complex electrochemistry is transforming the light from your computer screen into an image that your brain can understand. Dr Wendy Yue (Croucher Fellowship 2017) seeks to understand this process and shed light on how we see the world around us.

Yue earned her BSc in Biochemistry from the University of Hong Kong in 2008, setting her sights on attending graduate school. She enrolled in the Biochemistry, Cellular and Molecular Biology PhD programme at Johns Hopkins University School of Medicine the same year, remaining there for the next eight years.

During her research rotations as a PhD student, Yue began to develop an interest in neurobiology, and more specifically sensory biology. “Sensory neuroscience is interesting because it’s how we, as organisms, interact with each other and the natural world,” she explained.

To further this interest, she joined the lab of Dr King-Wai Yau, a professor of neuroscience and ophthalmology, who focuses on the flow of molecular signals that are significant in sight and smell. Yue was particularly interested in understanding the process of phototransduction, whereby light is absorbed by pigments and converted into neuronal signals.

Phototransduction is generally thought to occur within photoreceptor cells called rods and cones, which are the two major cell types within the retina. Rods allow us to see in low-light conditions but cannot detect colour. Cones, on the other hand, are colour-sensitive but require brighter conditions. Rods and cones work together to allow us to see images clearly.

Intrinsically photoreceptive retinal ganglion cells (ipRGCs), labeled here in red.

In addition to the well-known rods and cones, the retina also contains a third type of photoreceptor cells called intrinsically photoreceptive retinal ganglion cells (ipRGCs), which are responsible for some interesting phenomena within the field of visual biology.

For example, many forms of blindness are caused by the loss of rods and cones. However, researchers have observed something peculiar among these individuals. Despite having no conscious perception of light, they can still synchronise their internal circadian clocks to light/dark cycles in their environment, an unconscious process called circadian photoentrainment. In addition, their pupillary light reflex (contraction of the pupil in response to bright light) remains intact.

How can these people sense light while being completely blind? The answer lies in ipRGCs. These cells cannot form images, as rods and cones can, but they are still able to sense the brightness of our surroundings and relay that information to the brain. Yue and other members of her lab sought to further understand how phototransduction occurs in ipRGCs.

Previous studies with mouse models had focused on the M1 subtype of ipRGCs. In these cells, the pigment melanopsin is activated by light and triggers the opening of channels called TRPC6 and TRPC7.

Many researchers assumed that this pathway was the same for all subtypes of ipRGCs. Yue and her colleagues tested this by using genetic tools to inactivate the TRPC6 and TRPC7 genes.

As expected, the M1 cells were no longer responsive to light. However, other subtypes (M2 and M4) still maintained some or all of their light response. This suggested that another pathway exists in these ipRGC subtypes.

The team went on to discover that melanopsin was activating HCN, a different type of channel, in these ipRGC subtypes. M4 cells relied almost entirely on this alternative signalling pathway while M2 cells used both HCN and TRPC6/7 pathways.

The work was published in 2018 in Cell, with Yue as a co-author. While the paper showed the HCN pathway is sufficient for circadian photoentrainment and the pupillary light reflex, the relative contribution of these two pathways remains a topic of investigation.

In addition to her work on ipGRCs, Yue studied phototransduction in rod cells. Rods utilise a G protein-coupled receptor (GPCR) called rhodopsin to convert light into a cellular signal. GPCRs are widespread in biology and known for their ability to greatly amplify a small signal using intermediate messengers called G proteins, as well as downstream effector enzymes.

Rhodopsin was one of the first GPCRs to be characterised. Despite this, the degree of signal amplification in this pathway was never fully quantified. One photo-activated rhodopsin molecule was believed to activate hundreds of downstream effectors, but evidence for this remained inconclusive.

Yue and others in her lab utilised a weakened form of rhodopsin that could only activate up to one G protein molecule at a time. This allowed them to accurately quantify the signalling output of a single activated rhodopsin GPCR.

They found that the amplification of this pathway is only around 12 to 14-fold, much lower than the hundreds-fold that was previously reported. Since rhodopsin is such a prototypical GPCR, this finding suggests that other GPCRs might have less signal amplification than expected, a subject which future studies could investigate in more detail.

The research was published in the Proceedings of the National Academy of Sciences (PNAS) of the United States of America in 2019, with Yue as the first author.

As Yue neared the completion of her PhD, she knew that she wanted to continue working in cell signalling. “I like to be able to sit in front of cells doing recordings and seeing their responses in front of my eyes,” she explained.

However, she wanted to explore new sensory modalities outside vision as she had also become interested in senses in connection with pathological conditions, such as photophobia in migraine, while at Yau’s lab.

After finishing graduate school, Yue joined the lab of Dr David Julius at the University of California, San Francisco, in 2016, as a postdoctoral scholar. Her current research is focused on migraine pain, and she hopes to use her extensive background in visual signal transduction to now study how pain signalling occurs in the brain.

Dr Wendy Yue received her Bachelor of Science in Biochemistry from the University of Hong Kong in 2008. She then enrolled in the Biochemistry, Cellular and Molecular Biology PhD programme at Johns Hopkins University School of Medicine, joining Dr King-Wai Yau’s laboratory to study photoreception in animals. In 2016, she became a postdoctoral fellow in Dr David Julius’s laboratory at the University of California, San Francisco.

To view Wendy Yue’s Croucher profile, please click here.