Neurodegeneration in the central nervous system (CNS) due to trauma or disease can have devastating consequences on one’s quality of life. The retina is part of the CNS and a number of blinding eye diseases, like macular degeneration and glaucoma result from neurodegeneration in the retina. Although there are a variety of avenues for treating people with blinding eye disease, almost all these approaches involve invasive surgeries and introduction of foreign material into the eye with the risk of inflammation, rejection, and tumor formation. Ideally, we would like to develop strategies that stimulate the retina to repair itself via regeneration of neurons lost to injury or disease. Unfortunately, mammals are incapable of regenerating their CNS. However, hope comes from teleost fish like zebrafish that harbor robust regenerative powers and are able to repair a damaged CNS. Because the zebrafish and mammalian retina share structure and function, we suspect that mechanisms underlying retina regeneration in zebrafish will suggest strategies that can be applied to stimulate repair of the human retina.
Daniel J. Goldman, Ph. D.
Like mammals, the zebrafish retina harbors 6 major neuron types and 1 major glial cell type (named Müller glia). Normally, Müller glia contribute to retinal structure and homeostasis in both fish and mammals. However, in zebrafish, Müller glia also serve as a source of multipotent progenitors that repair a damaged retina and can restore sight. Underlying Müller glia’s regenerative response is a partial reprogramming of the Müller glia genome that prepares it for an asymmetric division that produces a progenitor that undergoes a limited number of cell divisions before it differentiates into one of the 6 major retinal neuron types.
Using a combination of molecular, cellular, and genetic approaches, the Goldman lab is determining the mechanisms underlying retina regeneration in zebrafish and using this information to guide strategies that aim to stimulate retina regeneration in mammals. Towards this goal we are investigating: 1) Müller glial cell heterogeneity to determine if subtypes exist and if particular subtypes are more prone to participate in retinal repair than others; 2) interspecies comparative analysis of fish and mice Müller glia gene expression and signal transduction pathways to identify those uniquely contributing to retina regeneration in zebrafish and perhaps critical for stimulating regeneration in mammals; and 3) developing AAV as a gene delivery tool to the mouse retina to test if regeneration-associated genes and signaling pathways identified in fish can stimulate mammalian Müller glia to mount a regenerative response. Through these efforts we hope to bring a regenerative approach to the clinic for treating blinding eye diseases resulting from neurodegeneration.
For more information please visit Goldman Faculty Profile.