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The basic-helix-loop-helix transcription factor ngn-1/neurogenin activates transcription of multiple terminal selector transcription factors in the Caenorhabditis elegans nervous system

ABSTRACT: Proper nervous system development is required for an organism’s survival and function. Defects in neurogenesis have been linked to neurodevelopmental disorders such as schizophrenia and autism spectrum disorders. Understanding the gene regulatory networks that orchestrate neural development, specifically cascades of proneural transcription factors, can better elucidate which genes are most essential in governing early neurogenesis. Neurogenins are a family of such factors that are both sufficient and necessary for the development of neural sub-types in mice, primarily through the regulation of other factors, particularly neurod. The objective of this study was to evaluate previously established regulatory targets of neurogenin (ngn-1) and to identify unknown downstream targets, using the nematode Caenorhabditis elegans as a model for these studies. We find that in C. elegans, neurogenin is required for axon outgrowth, cell fate specification, and epithelial integrity during embryonic development. Using RNA sequencing and comparative transcriptome analysis we found that ngn-1 acts primarily to repress transcription, facilitating proper embryogenesis. We also identified specific candidates for activation by ngn-1, including hlh-34(npas1) and unc-42(prop1), which we further validated using genetic methods. Our results identify novel pathways connecting ngn-1 to known terminal regulators, which maintain cell fate of terminally differentiated neural subtypes, and align neurogenins within the larger context of proneural transcription factors.

ORGANISM(S): Caenorhabditis elegans

PROVIDER: GSE143599 | GEO | 2020/06/16

REPOSITORIES: GEO

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Project description:Transcriptional targets of neurogenin (Ngnr1) were identified by over-expression of an inducible form of neurogenin in Xenopus ectodermal explants. The effects of co-expressing the nucleoprotein geminin on Ngnr1-dependent target gene transactivation were defined. Regulating the transition from lineage-restricted progenitors to terminally differentiated cells is a central aspect of nervous system development. Here, we investigated the role of the nucleoprotein geminin in regulating neurogenesis at a mechanistic level during both Xenopus primary neurogenesis and mammalian neuronal differentiation in vitro. The latter work utilized both neural cells derived from embryonic stem and embryonal carcinoma cells in vitro and neural stem cells from mouse forebrain. In all of these contexts, geminin antagonized the ability of neural bHLH transcription factors to activate transcriptional programs promoting neurogenesis. Furthermore, geminin promoted a bivalent chromatin state, characterized by the presence of both activating and repressive histone modifications, at genes encoding transcription factors that promote neurogenesis. This epigenetic state restrains the expression of genes that regulate commitment of undifferentiated stem and neuronal precursor cells to neuronal lineages. Geminin is highly expressed in undifferentiated neuronal precursor cells but is downregulated prior to differentiation. Therefore, these data support a model whereby geminin promotes the neuronal precursor cell state by modulating both the epigenetic status and expression of genes encoding neurogenesis-promoting factors. Additional developmental signals acting in these cells can then control their transition toward terminal neuronal or glial differentiation during mammalian neurogenesis. A dexamethasone-inducible (GR ligand binding domain fused) form of Xenopus neurogenin-related 1, NgnrGR, was over-expressed in Xenopus embryonic ectodermal explants, in the presence or absence of over-expressed geminin. Induction of Ngnr1 activity was used to define direct targets as previously described (EMBO J. 26(24): 5093-5108). The ability of geminin to suppress Ngnr1-dependent transactivation of its target gene programs was determined.

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The basic-helix-loop-helix transcription factor ngn-1/neurogenin activates transcription of multiple terminal selector transcription factors in the Caenorhabditis elegans nervous system

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