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

Transdifferentiation, or direct cell reprogramming, is the direct conversion of one fully differentiated cell type into another. Whether core mechanisms are shared between different transdifferentiation events, which can occur naturally in presence or in absence of cell division, is unclear. Our lab has previously characterized the Y-to-PDA natural transdifferentiation in Caenorhabditis elegans, which occurs without cell division and requires orthologs of vertebrates reprogramming factors. In this study, focusing on another transdifferentiation process, the K rectal cell-to-DVB GABAergic neuron, we report that the Y-to-PDA reprogramming factor SEM-4/SALL, SOX-2, CEH-6/POU are required for K-to-DVB transdifferentiation to allow the erasure of the rectal identity. In addition, cell division is necessary but not sufficient for this transdifferentiation event while the Wnt signaling plays distinct functions during the process including the selection of the daughter cell with a different fate, loss of the rectal identity and imposition of the specific neuronal subtype identity. We provide evidence that both the Wnt signaling and Y-to-PDA reprogramming factor SEM-4/SALL, SOX-2, CEH-6/POU act in parallel for the rectal identity erasure. Our results further support a model where antagonistic activities of SOX-2 and POP-1 and decreasing SOX-2 levels over time provide a timer for the acquisition of the final identity. In addition, the different levels of SOX-2 provide a mechanism for the integration of Wnt opposite dedifferentiation and re-differentiation functions during K-to-DVB transdifferentiation.