A natural transdifferentiation event involving mitosis is empowered by integrating signaling inputs with conserved plasticity factors

• Published in: Cell reports (Cambridge) 2022-09, Vol.40 (12), p.111365-111365, Article 111365
• Main Authors: Riva, Claudia, Hajduskova, Martina, Gally, Christelle, Suman, Shashi Kumar, Ahier, Arnaud, Jarriault, Sophie
• Format: Article
• Language: English
• Subjects: Animals; C. elegans; Caenorhabditis elegans - metabolism; Caenorhabditis elegans Proteins - genetics; Caenorhabditis elegans Proteins - metabolism; Cell Transdifferentiation; cell type conversion; Cellular Biology; Development Biology; EGL-5/HOX; Genetics; Life Sciences; Mitosis; natural direct reprogramming; OCT4; SALL4; SOX2; Subcellular Processes; TF dosage; transition state; Wnt; Wnt Signaling Pathway
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2022.111365

Transdifferentiation, or direct cell reprogramming, is the conversion of one fully differentiated cell type into another. Whether core mechanisms are shared between natural transdifferentiation events when occurring with or without cell division is unclear. We have previously characterized the Y-to-PDA natural transdifferentiation in Caenorhabditis elegans, which occurs without cell division and requires orthologs of vertebrate reprogramming factors. Here, we identify a rectal-to-GABAergic transdifferentiation and show that cell division is required but not sufficient for conversion. We find shared mechanisms, including erasure of the initial identity, which requires the conserved reprogramming factors SEM-4/SALL, SOX-2, CEH-6/OCT, and EGL-5/HOX. We also find three additional and parallel roles of the Wnt signaling pathway: selection of a specific daughter, removal of the initial identity, and imposition of the precise final subtype identity. Our results support a model in which levels and antagonistic activities of SOX-2 and Wnt signaling provide a timer for the acquisition of final identity. [Display omitted] •Transdifferentiation occurs naturally with or without cell division in C. elegans•Wnt selects the daughter cell which transdifferentiates in presence of division•Conserved plasticity factors and Wnt act in parallel to erase the initial identity•Changes in stoichiometry of SOX-2 and TCF could control timing of re-differentiation Using single-cell natural transdifferentiation models in C. elegans, Riva et al. demonstrate that conserved and event-specific mechanisms allow transdifferentiation with or without cell division. Although evolutionary-conserved plasticity factors are required independently of cell division, Wnt signaling activity is context dependent. Dichotomic interactions between SOX-2 and Wnt may control re-differentiation timing.