Novel Regulatory Mechanisms for the SoxC Transcriptional Network Required for Visual Pathway Development

Abstract

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 , and is sufficient to differentiate human induced pluripotent stem cells into electrophysiologically active RGCs. These data place Sox4 downstream of RE1 silencing transcription factor in regulating RGC fate, and further describe a newly identified, Sox4-regulated site for post-translational modification with small ubiquitin-related modifier (SUMOylation) 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 ∼14% of all diagnosed patients. Differentiated and transplanted RGC-like cells derived from stem cells have the potential to replace neurons that have already been lost and thereby to restore visual function. These data uncover new mechanisms of retinal progenitor cell (RPC)-to-RGC and human stem cell-to-RGC fate specification, and take a significant step toward understanding neuronal and retinal development and ultimately cell-transplant therapy.

Single cell transcriptomics reveals lineage trajectory of the retinal ganglion cells in wild-type andAtoh7-null retinas

“…We propose that the SoxC family of transcription factors, including Sox4 and Sox11, fulfill this role ( Figure 10). This is based on previous reports that deletion of the SoxC genes leads to severely compromised RGC production [97][98][99] , and our finding that they are expressed at high levels in the transitional RPCs and that their expression is not dependent on Atoh7. The SoxC factors likely also function in differentiating RGCs and other cell types, as they continue to be expressed in fate-committed retinal neurons.…”

“…The scRNA-seq data also clarified contradicting results on two genes critical in retinal development. Sox4 and Sox11, which encodes two transcription factors critical for RGC development [97][98][99] , have been identified to be expressed mostly in RGCs, but there have been conflicting reports regarding whether they are also expressed in RPCs 59,[98][99][100] . In the Atoh7-null retina, since most RGCs are absent, it was indicated that Sox4 and Sox11 were downregulated 59,98 .…”

Sox11 Expression Promotes Regeneration of Some Retinal Ganglion Cell Types but Kills Others

“…Our results suggest Sox11 is one such critical factor. Both Sox11 and Sox4 are members of the Sry-related high mobility group (HMG) box (SOX) family of transcription factors which have been implicated as critical regulators of cell fate, differentiation, and survival during development (Sarkar and Hochedlinger, 2013; Chang et al, 2017; Kuwajima et al, 2017). Sox11 promoted strong and significant axonal regeneration, and Sox4 likely promoted regeneration albeit with marginal significance.…”

Phosphorylation of the neurogenic transcription factor SOX11 on serine 133 modulates neuronal morphogenesis

“…Recent data suggests that SOX11 activity may be controlled not only by epigenetic and transcriptional mechanisms, but also by post-translational modifications. In retinal ganglion cells, SOX11’s subcellular localization is modulated by SUMOylation 10 . In previous work we identified ten candidate serine residues for phosphorylation via mass spectrometry.…”