[Seminar] "Stimulating Photoreceptor Regeneration from Muller Cells in Zebrafish Models of Inherited Retinal Dystrophy" by Prof. Brian Perkins

Abstract:
Inherited forms of blindness affect approximately 1 in 3000 people worldwide. The zebrafish (Danio rerio) represents an ideal system for study because, unlike mammals, zebrafish can regenerate damaged retinal neurons following intense light damage, mechanical injury, or chemical toxicity. Central to this regenerative response is the de-differentiation and reprogramming of Müller glia into multipotent stem cell progenitors. It is often assumed that adult zebrafish will regenerate lost neurons, particularly photoreceptors, in disease states, but this viewpoint overlooks multiple examples of progressive retinal degeneration in zebrafish. The zebrafish cep290-/-, bbs2-/- and eys-/- mutants are models of human retinal dystrophies. All mutants are viable to at least 1 year of age and exhibit photoreceptor degeneration. Our data on cep290-/-, bbs2-/- and eys-/- mutants reveals a significant increase in the proliferation of rod precursor cells, but little to no proliferation of Müller glia, thus resulting in a net loss of cone photoreceptors over time. In response to acute injury, the Müller glia proliferate and regenerate new photoreceptors. Regeneration is not complete, however, suggesting that the disease environment limits the capacity for regeneration. Mutants show signs of inflammation, including activating microglia. Immune suppression blocks proliferation of rod progenitors, suggesting the immune response contributes to regeneration.

Biography:
Brian Perkins was born in Abilene, Texas (USA). He received his B.S. degree from Abilene Christian University in 1995 and a Ph.D. from Baylor College of Medicine in 2000. He studied under the guidance of Drs. John Wilson and Ted Wensel explored the use of triplex DNA to generate double-strand breaks at specific targets in the rhodopsin gene. From 2000-2004, Dr. Perkins conducted postdoctoral work at Harvard University with Dr. John Dowling, where he conducted multiple genetic screens for zebrafish mutants of photoreceptor degeneration and developed tools to study photoreceptor mutants.

He joined the faculty at Texas A&M as an Assistant Professor and was promoted, with tenure, to Associate Professor in 2011. In 2012, he moved to the Cole Eye Institute at the Cleveland Clinic where he continues to use zebrafish, as well as patient-derived induced pluripotent stem cells (iPSCs) to study retinal degeneration. During his career in vision research, he has identified several mutants affecting photoreceptor survival and conducted studies of zebrafish Intraflagellar Transport mutants and other genes that lead to photoreceptor degeneration. Among the contributions to the field, his group was the first to directly demonstrate the essential role of cytoplasmic dynein II as a motor in photoreceptors and were the first to document a differential role for Ift57 and Ift88 proteins in vivo. They were the first to show that zebrafish do not exhibit the same deficiencies in Hh signaling as mammals. He has conducted studies of microRNAs in zebrafish and found that the miR-183/96/182 cluster is essential for normal vestibular function in zebrafish but dispensable for retina function. Finally, we have demonstrated that zebrafish cep290 mutants exhibit progressive cone degeneration without significant regeneration. This model will enable us to define the degree of photoreceptor death required to trigger regeneration in zebrafish.