Study IDs Transcription Factors Leading to 4 Cell Types in Retina

Their study — published in the Proceedings of the National Academy of Sciences — suggests that the gene-regulating proteins Onecut1 and Onecut2 play a more significant role in the development of the vision system in mammals than was previously appreciated.

Also, because these related transcription factors are expressed in other tissues during development, the study suggests what drives cellular formation in other parts of the nervous system, including the spinal cord.

Mu and his team found that mice lacking both transcription factors had other significant losses, including abnormal development of cones (a photoreceptor cell type), retinal ganglion cells and amacrine cells.

“All these cell types are essential for normal vision, and defects in any of them can lead to vision loss, even blindness,” explains Xiuqian Mu, MD, PhD, senior author and assistant professor of ophthalmology and biochemistry.

Previously, the UB researchers found that the same transcription factors are responsible for normal development of horizontal cells, which allow eyes to adjust to bright and dim light.

“Development of the vision system, including the retina, is a complex but tightly regulated process,” Mu explains. 

The retina develops through two waves of cell type formation: early and late.

“Each wave leads to the development of several cell types, and our study found that Onecut1 and Onecut2 regulate the first wave,” he says.

The genetic basis for these waves and why there are two has been a mystery, he adds.

In illuminating processes related to one of the waves, the study “sheds light on how the generation of different retinal cell types is coordinated,” says Mu.

The study shows how these transcription factors have overlapping responsibilities for the same cells or, in other words, how they redundantly regulate cellular diversity in the retina.

“Transcription factors are the most important regulators in the development of various organs, including the vision system in mammals,” explains Mu. “They turn on and off the genes required for normal development.” 

Understanding normal development is key to developing therapies for many genetic diseases, including genetic eye diseases, Mu notes. 

“It is conceivable that in the future we will learn that mutations in these genes cause defects in the human retina,” he says.

“Through one approach now under development, many scientists are trying to generate functional retinal neurons in culture to replace diseased ones,” says Mu. “Conceivably, what we learned here may in the future be applied to such efforts.”

Darshan Sapkota, PhD, a graduate of UB’s biochemistry doctoral program who studied under Mu, is first author on the paper, “Onecut1 and Onecut2 Redundantly Regulate Early Retinal Cell Fates During Development.” Sapkota is now a postdoctoral fellow at Washington University in St. Louis.

Other co-authors from the Department of Ophthalmology are:

• Hemabindu Chintala, PhD, postdoctoral associate
• Fuguo Wu, PhD, research scientist
• Steven J. Fliesler, PhD, Meyer H. Riwchun Endowed Chair Professor, vice-chair and director of research; professor of biochemistry; and research health scientist, VA Western New York Healthcare System (VAWNYHS)

Zihua Hu, PhD, bioinformatics computational scientist at UB’s Center for Computational Research and adjunct assistant professor of biostatistics, also contributed.

Several of the scientists have conducted research through the Developmental Genomics Group in UB’s New York State Center of Excellence in Bioinformatics and Life Sciences, where Mu’s lab is located.

The study was funded by the National Eye Institute, the Whitehall Foundation, the SUNY Research Collaboration Fund and Research to Prevent Blindness. VAWNYHS provided resources and facilities.