Research in Focus is a series that highlights Neurobiology faculty members’ papers in peer-reviewed journals.
A study led by Alecia K. Gross, Ph.D., professor and vice chair for Research and Research Infrastructure in the Department of Neurobiology, was published in the Federation of American Societies for Experimental Biology (FASEB) Journal for the paper “NUDC is critical for rod photoreceptor function, maintenance, and survival.”
The first author was Mary Ann Garner, Ph.D., assistant professor in the Department of Neurobiology, and several trainees also contributed to the study, as well as faculty from the University of Utah’s Department of Ophthalmology and Visual Sciences.
The paper studies rod photoreceptors—specialized neurons in the retina that capture light in dim conditions. Their recent research has highlighted the crucial role of nuclear distribution protein c (NUDC) in these cells, filling a significant gap in scholarship on NUDC in the retina.
The study used a mouse model to knock out NUDC specifically in rod photoreceptors, avoiding widespread neurodegeneration. This research highlights NUDC’s critical role in these neurons, revealing rapid functional declines and structural issues when NUDC is absent.
To better understand the importance of this study, we sat down with Garner to discuss research findings.
Q: Can you describe the key findings of your recent publication?
This paper investigated the role of nuclear distribution protein c (NUDC) in rod photoreceptors, the neurons in the retina that capture photons of light in dim light conditions. NUDC is a protein that is involved in mitotic cell division and transportation along microtubules, and we found that loss of NUDC in rod photoreceptors caused mislocalization of the light-capturing rhodopsin, early functional losses, glial reactivity, ultrastructural abnormalities, and ultimately, rod photoreceptor degeneration.
Q: What inspired you to pursue this area of research?
Knocking NUDC out in a rod photoreceptor is an ideal way to study the postmitotic functions of this protein in a neuronal cell without causing devastating neurodegeneration. NUDC is a difficult protein to study in postmitotic cells since it is required for cell division. In other words, if we knocked out NUDC globally, an organism would not get past the one-cell stage. In our mouse model, NUDC was knocked out only in rod photoreceptors at P7-P8, which ensured that the rods cells developed and their outer segments – the portion of the rod photoreceptor that is full of the light-capturing protein rhodopsin – were beginning to form.
Q: How does your discovery advance our understanding of the brain and its functions?
Rods are highly specialized central nervous system neurons, and this research advances our understanding of the critical role of NUDC in postmitotic neurons in general and in rod photoreceptors in particular.
Q: Were there any surprising or unexpected results in your research?
We were surprised by the rapid functional losses in the mice lacking NUDC in rods alone. By three weeks, these mice showed decreases in rod function that were completely lost by six weeks of age. Additionally, the transmission electron microscopy (TEM) data showing the ultrastructural differences in the rods lacking NUDC showed some rods with overgrown disks while others exhibited abnormalities in the structure of the inner segment. Both of these could be attributed to abnormalities with the actin cytoskeleton (see Q8).
Q: How do you plan to build on this research in your future studies?
NUDC interacts with another protein called cofilin 1 (CFL1). Unphosphorylated CFL1 normally binds to the actin cytoskeleton and is an effector of actin cytoskeletal reorganization. In this work, we found that NUDC and CFL1 were located in close proximity to one another in the rod inner segment and that loss of NUDC increased the pool of phosphorylated CFL1, which would affect its ability to bind to actin. CFL1 has been widely studied in the brain, however its role in retinal neurons is unknown. Our current work focuses on the role of CFL1 in rods and cones. This is especially important considering the important role of actin at the base of the outer segment as well as at the synapse.
This study was contributed to by the following former trainees and colleagues: Meredith Hubbard, M.D., organ procurement specialist in the Legacy of Hope at UAB; Evan Boitet, Ph.D., assistant professor at Jefferson State Community College; Seth Hubbard, postbaccalaureate student at the National Institute of Health; Anushree Gade, medical student; Guoxin Ying, Ph.D., research assistant professor at the University of Utah; Bryan Jones, Ph.D., associate professor at the University of Utah; and Wolfgang Baehr, professor at the University of Utah.