What pathways specify retinal ganglion cell (RGC) fate in the developing retina? Here we report on mechanisms by which a molecular pathway involving Sox4/Sox11 is required for RGC differentiation and for optic nerve formation in mice in vivo, and is sufficient to differentiate human induced pluripotent stem cells into electrophysiologically active RGCs. These data place Sox4 downstream of RE1 silencing transcription factor (REST) in regulating RGC fate, and further describe a newly identified, Sox4-regulated SUMOylation site in Sox11, which suppresses Sox11's nuclear localization and its ability to promote RGC differentiation, providing a mechanism for the SoxC familial compensation observed here and elsewhere in the nervous system. These data define novel regulatory mechanisms for this SoxC molecular network, and suggest pro-RGC molecular approaches for cell replacement-based therapies for glaucoma and other optic neuropathies.
Glaucoma is the most common cause of blindness worldwide and along with other optic neuropathies is characterized by loss of retinal ganglion cells (RGCs). Unfortunately, vision and RGC loss are irreversible, and lead to bilateral blindness in around 14% of all diagnosed patients. Differentiating and transplanting RGC-like cells derived from stem cells have the potential to replace neurons that have already been lost and thereby restore visual function. These data uncover new mechanisms of retinal progenitor cell (RPC)- and human stem cell-to-RGC fate specification, and take a significant step towards understanding neuronal and retinal development and ultimately cell transplant therapy.
The authors declare that there are no conflicts of interest.
This work was supported by the Hope for Vision foundation, the National Eye Institute (P30 EY014081, Univ. Miami), an unrestricted grant from Research to Prevent Blindness, and the Walter G. Ross Distinguished Chair in Ophthalmic Research. JH was supported in part by NIH T32-NS07492, and by a Lois Pope Life Fellowship. We are grateful to Cheryl Craft for generously donating the cone-specific arrestin antibody, to Veronique Lefebvre for floxed Sox4, floxed Sox11 and Sox12 null alleles, to Eleut Hernandez for animal husbandry, to Gabriel Gaidosh for assistance with microscopy, to Waitt Advanced Biophotonics Center at the Salk Institute for assistance with electron microscopy and data analysis, and to Alexander Kreymerman, Suqian Wu and Xin Xia for their technical help.