Restoration of vision after de novo genesis of rod photoreceptors in mammalian retinas

Abstract

In zebrafish, Müller glial cells (MGs) are a source of retinal stem cells that can replenish damaged retinal neurons and restore vision ¹ . In mammals, however, MGs lack regenerative capability as they do not spontaneously re-enter the cell cycle to generate a population of stem/progenitor cells that differentiate into retinal neurons. The regenerative machinery may exist in the mammalian retina, however, as retinal injury can stimulate MG proliferation followed by limited neurogenesis ^{2– 7} . The fundamental question remains whether MG-derived regeneration can be exploited to restore vision in mammalian retinas. Previously, we showed that gene transfer of β-catenin stimulates MG proliferation in the absence of injury in mouse retinas ⁸ . Here, we report that following gene transfer of β-catenin, cell-cycle-reactivated MGs can be reprogrammed into rod photoreceptors via a subsequent gene transfer of transcription factors that are essential for rod cell fate specification and determination. MG-derived rods restored visual responses in Gnat1 ^rd17 : Gnat2 ^cpfl3 double mutant mice, a model of congenital blindness ^{9, 10} , throughout the visual pathway from the retina to the primary visual cortex. Together, our results provide evidence of vision restoration after de novo MG-derived genesis of rod photoreceptors in mammalian retinas.