title: The transcription factor Nerfin-1 prevents reversion of neurons into neural stem cells.
abstract: Cellular dedifferentiation is the regression of a cell from a specialized state to a more multipotent state and is implicated in cancer. However, the transcriptional network that prevents differentiated cells from reacquiring stem cell fate is so far unclear. Neuroblasts (NBs), the Drosophila neural stem cells, are a model for the regulation of stem cell self-renewal and differentiation. Here we show that the Drosophila zinc finger transcription factor Nervous fingers 1 (Nerfin-1) locks neurons into differentiation, preventing their reversion into NBs. Following Prospero-dependent neuronal specification in the ganglion mother cell (GMC), a Nerfin-1-specific transcriptional program maintains differentiation in the post-mitotic neurons. The loss of Nerfin-1 causes reversion to multipotency and results in tumors in several neural lineages. Both the onset and rate of neuronal dedifferentiation in nerfin-1 mutant lineages are dependent on Myc- and target of rapamycin (Tor)-mediated cellular growth. In addition, Nerfin-1 is required for NB differentiation at the end of neurogenesis. RNA sequencing (RNA-seq) and chromatin immunoprecipitation (ChIP) analysis show that Nerfin-1 administers its function by repression of self-renewing-specific and activation of differentiation-specific genes. Our findings support the model of bidirectional interconvertibility between neural stem cells and their post-mitotic progeny and highlight the importance of the Nerfin-1-regulated transcriptional program in neuronal maintenance.
authors.affiliation: Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria 3010, Australia;
authors.forename: Francesca
authors.initials: F
authors.lastname: Froldi
authors.affiliation: Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria 3010, Australia;
authors.forename: Milan
authors.initials: M
authors.lastname: Szuperak
authors.affiliation: Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria 3010, Australia;
authors.forename: Chen-Fang
authors.initials: CF
authors.lastname: Weng
authors.affiliation: Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia; Department of Computing and Information Systems, The University of Melbourne, Parkville, Victoria 3010, Australia;
authors.forename: Wei
authors.initials: W
authors.lastname: Shi
authors.affiliation: Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria 3010, Australia; Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia; Department of Medical Biology, University of Melbourne, Melbourne, Victoria 3010, Australia.
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Papenfuss
authors.affiliation: Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria 3010, Australia; louise.cheng@petermac.org.
authors.forename: Louise Y
authors.initials: LY
authors.lastname: Cheng
mesh_terms: D000818:Animals; D054337:Cell Dedifferentiation / Q000235:genetics*; D002454:Cell Differentiation / Q000235:genetics; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000166:cytology* / Q000235:genetics / Q000254:growth & development; D018507:Gene Expression Regulation, Developmental; D009154:Mutation; D058953:Neural Stem Cells / Q000166:cytology*; D055495:Neurogenesis / Q000235:genetics / Q000502:physiology*; D009474:Neurons / Q000166:cytology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D029721:Drosophila Proteins; D014157:Transcription Factors; C418490:nerfin-1 protein, Drosophila
keywords: Drosophila; cancer; central nervous system; dedifferentiation; neuroblasts; stem cells