Investigating the unexpected role of transport motors inside light-detector cells
- Type of funding: Project Grant
- Grant Holder: Dr Andrew Peden
- Institute: University of Sheffield
- Region: North East
- Start date: October 2016
- End Date: March 2020
- Priority: Causes
- Eye Category: Inherited retinal
Photoreceptors are the cells in the eye that detect light. Like other cells in the body, they have hair-like antennas (called cilia) that stick out from the cell’s surface and sense the environment. Photoreceptor cilia are very specialised – without them, photoreceptors are blind to light and will die.
Making photoreceptor cilia involves transporting proteins from the cell body. This is done by other, ‘motor’, proteins that travel along inside the cell on ‘railroad tracks’ called microtubules. They’re also in constant use when photoreceptors are working. Without these transport motors, the cilia don’t get built.
The research team has been studying what the photoreceptor cilia motors do and have turned up some unexpected findings. First, the motors are involved at an earlier stage of building cilia than was known about. The team thinks this might be linked to a group of proteins that are involved in Usher syndrome, which causes blindness due to retinitis pigmentosa.
They also found that cilia motors may affect the cell’s internal waste disposal process (autophagy) for clearing up unnecessary and wrongly-placed proteins. This could add to their effect on photoreceptor survival. The team is trying to find out.
Finally, they’ve found that the motors might control production of the pigments that actually detect light (proteins called opsins). They want to find out how.Results from the study will help us understand more about how proteins linked to inherited retinal disorders work. That’s important for developing treatments. They also aim to find substances that can slow or stop photoreceptor cell death.
Novel roles of ciliary kinesins in photoreceptor differentiation and survivalThe cilium is an essential part of the photoreceptor cell. The detection of light takes place in the photoreceptor cilium. Without cilia photoreceptors are completely dysfunctional and even subtle defects of ciliary function lead to photoreceptor degeneration and blindness.
The formation of cilia in general, and photoreceptor cilia in particular, requires microtubule dependent motors, kinesins. The research team has studied the function of the kif3a gene, which encodes the main motor subunit of the ciliary kinesin. Their studies led to unexpected findings.
First, they found that kif3a is necessary not just for cilia formation but also functions at an earlier stage of ciliogenesis: the docking of the ciliary basal body to the cell membrane. They will use molecular genetic approaches in the zebrafish model to determine the mechanism of this function.
Second, the team found that, surprisingly, photoreceptor degeneration is slower in kif3a mutants, compared to mutations in related IFT genes. This is of interest as it may lead to mechanisms that regulate photoreceptor survival. Again, they will use zebrafish genetics and pharmacological approaches to explore these mechanisms.
Finally, they also found evidence that microtubule-dependent motors regulate the expression of the visual pigment, opsin. This suggests an entirely new mechanism that regulates opsin expression and photoreceptor differentiation. The team plans to determine the genetic components of this mechanism by testing candidate genes and screening for compounds that interfere with its function. Overall, these studies will reveal mechanisms fundamental to photoreceptor differentiation and survival and provide new ways of slowing down photoreceptor loss in human ciliopathies.