Dataset Information

Opposing Effects of Growth and Differentiation Factors in Cell-Fate Specification.

ABSTRACT: Following ocular trauma or in diseases such as glaucoma, irreversible vision loss is due to the death of retinal ganglion cell (RGC) neurons. Although strategies to replace these lost cells include stem cell replacement therapy, few differentiated stem cells turn into RGC-like neurons. Understanding the regulatory mechanisms of RGC differentiation in vivo may improve outcomes of cell transplantation by directing the fate of undifferentiated cells toward mature RGCs. Here, we report a new mechanism by which growth and differentiation factor-15 (GDF-15), a ligand in the transforming growth factor-beta (TGF-?) superfamily, strongly promotes RGC differentiation in the developing retina in vivo in rodent retinal progenitor cells (RPCs) and in human embryonic stem cells (hESCs). This effect is in direct contrast to the closely related ligand GDF-11, which suppresses RGC-fate specification. We find these opposing effects are due in part to GDF-15's ability to specifically suppress Smad-2, but not Smad-1, signaling induced by GDF-11, which can be recapitulated by pharmacologic or genetic blockade of Smad-2 in vivo to increase RGC specification. No other retinal cell types were affected by GDF-11 knockout, but a slight reduction in photoreceptor cells was observed by GDF-15 knockout in the developing retina in vivo. These data define a novel regulatory mechanism of GDFs' opposing effects and their relevance in RGC differentiation and suggest a potential approach for advancing ESC-to-RGC cell-based replacement therapies.

SUBMITTER: Chang KC

PROVIDER: S-EPMC6581615 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Opposing Effects of Growth and Differentiation Factors in Cell-Fate Specification.

Chang Kun-Che KC Sun Catalina C Cameron Evan G EG Madaan Ankush A Wu Suqian S Xia Xin X Zhang Xiong X Tenerelli Kevin K Nahmou Michael M Knasel Cara M CM Russano Kristina R KR Hertz Jonathan J Goldberg Jeffrey L JL

Current biology : CB 20190530 12

Following ocular trauma or in diseases such as glaucoma, irreversible vision loss is due to the death of retinal ganglion cell (RGC) neurons. Although strategies to replace these lost cells include stem cell replacement therapy, few differentiated stem cells turn into RGC-like neurons. Understanding the regulatory mechanisms of RGC differentiation in vivo may improve outcomes of cell transplantation by directing the fate of undifferentiated cells toward mature RGCs. Here, we report a new mechani ...[more]

PMID: 31155355

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Project description:In the nervous system, the specific identity of a neuron is established and maintained by terminal selector transcription factors that directly activate large batteries of terminal differentiation genes and positively regulate their own expression via feedback loops. However, how this is achieved in a reliable manner despite noise in gene expression, genetic variability or environmental perturbations remains poorly understood. We addressed this question using the AIY cholinergic interneurons of C. elegans, whose specification and differentiation network is well characterized. Via a genetic screen, we found that a loss of function of PRC1 chromatin factors induces a stochastic loss of AIY differentiated state in a small proportion of the population. PRC1 factors act directly in the AIY neuron and independently of PRC2 factors. By quantifying mRNA and protein levels of terminal selector transcription factors in single neurons, using smFISH and CRISPR tagging, we observed that, in PRC1 mutants, terminal selector expression is still initiated during embryonic development but the level is reduced, and expression is subsequently lost in a stochastic manner during maintenance phase in part of the population. We also observed variability in the level of expression of terminal selectors in wild type animals and, using correlation analysis, established that this noise comes from both intrinsic and extrinsic sources. Finally, we found that PRC1 factors increase the resistance of AIY neuron fate to environmental stress, and also secure the terminal differentiation of other neuron types. We propose that PRC1 factors contribute to the consistency of neuronal cell fate specification and maintenance by protecting neurons against noise and perturbations in their differentiation program. Author summary During development, a high diversity of neuronal cell types is produced and they subsequently maintain their identity throughout the life of the animal. How this is achieved in a manner that is both accurate and robust to perturbations remains poorly understood. Terminal selector transcription factors play a key role in the specification and maintenance of neuron type identities. In this study, we observed that their expression is noisy. We also found that PRC1 chromatin factors contribute to the consistency of neuronal cell fate specification and maintenance. They help to set the correct level of terminal selector expression during the specification phase, and they secure the maintenance of terminal selector expression at later stages. PRC1 factors also increase the resistance of neuronal identity to environmental stress.

Dataset Information

Opposing Effects of Growth and Differentiation Factors in Cell-Fate Specification.

Publications

Opposing Effects of Growth and Differentiation Factors in Cell-Fate Specification.

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