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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 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 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.SIGNIFICANCE STATEMENT 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.

SUBMITTER: Chang KC

PROVIDER: S-EPMC5426184 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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

Chang Kun-Che KC Hertz Jonathan J Zhang Xiong X Jin Xiao-Lu XL Shaw Peter P Derosa Brooke A BA Li Janet Y JY Venugopalan Praseeda P Valenzuela Daniel A DA Patel Roshni D RD Russano Kristina R KR Alshamekh Shomoukh A SA Sun Catalina C Tenerelli Kevin K Li Chenyi C Velmeshev Dmitri D Velmeshev Dmitri D Cheng Yuyan Y Boyce Timothy M TM Dreyfuss Alexandra A Uddin Mohammed S MS Muller Kenneth J KJ Dykxhoorn Derek M DM Goldberg Jeffrey L JL

The Journal of neuroscience : the official journal of the Society for Neuroscience 20170414 19

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 <i>in vivo</i>, 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, S ...[more]

PMID: 28411269

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Project description:Though the bacterial transcription regulation apparatus is distinct in terms of several structural and functional features from its eukaryotic counterpart, the gross structure of the transcription regulatory network (TRN) is believed to be similar in both superkingdoms. Here, we explore the fine structure of the bacterial TRN and the underlying "co-regulatory network" (CRN) to show that despite the superficial similarities to the TRN of the eukaryotic model organism yeast, the bacterial networks display entirely different organizational principles. In particular unlike in eukaryotes, hubs of the bacterial networks are both global regulators and integrators of diverse disparate transcriptional responses. These and other organizational differences might correlate with the fundamental differences in gene and promoter organization in the two superkingdoms, especially the presence of operons and regulons in bacteria. Further we explored to find the interplay, if any, between network structures, mode of regulatory interactions and signal sensing of transcription factors (TFs) in shaping up the bacterial transcriptional regulatory responses. For this purpose, we first classified TFs according to their regulatory mode (activator, repressor or dual regulator) and sensory mechanism (one-component systems responding to internal or external signals, TFs from two-component systems and chromosomal structure modifying TFs) in the bacterial model organism Escherichia coli and then we studied the overall evolutionary optimization of network structures. The incorporation of TFs in different hierarchical elements of the TRN appears to involve on a multi-dimensional selection process depending on regulatory and sensory modes of TFs in motifs, co-regulatory associations between TFs of different functional classes and transcript half-lives. As a result it appears to have generated circuits that allow intricately regulated physiological state changes. We identified the biological significance of most of these optimizations, which can be further used as the basis to explore similar controls in other bacteria. We also show that, though on the larger evolutionary scale, unrelated TFs have evolved to become hubs, within lineages like gamma-proteobacteria there is strong tendency to retain hubs, as well as certain higher-order network modules that have emerged through lineage specific paralog duplications.

Dataset Information

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

Publications

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

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