Transdifferentiation is the direct conversion of one differentiated cell type into another, with or without cell division. In C. elegans the Y rectal cell naturally transdifferentiates into the PDA motor neuron with high efficiency, robustness and irreversibly and this process requires evolutionary conserved reprogramming factors. In this study our goal was to define in C. elegans which core and event-specific factors are affecting different natural transdifferentiations (Td). Looking at the worm's somatic cell lineage (Sulston et al., 1977), we postulated that the formation of the DVB GABAergic neuron from the K.p cell after K rectal cell division is another putative Td event. We confirmed that it is bona fide Td by analysing the cellular morphology and identity-specific markers in K and DVB. We assessed the role of Y-to-PDA reprogramming factors in K-to-DVB through genetic analyses. Based on
unc-47 expression and presence of an axon, we found that
sem-4,
egl-5,
sox-2 and
ceh-6 are also involved in K-to-DVB, suggesting that these factors have conserved reprogramming properties in the worm. The characterization of
sem-4 mutant revealed a defect in the erasure of the K.p initial rectal identity and in the gain of the neuronal one. We have found that during K-to-DVB a stereotyped, asymmetric cell division (ACD) occurs, with the K.p cell budding off. We have therefore investigated the potential role of cell division in this reprogramming event. The asymmetry of K division led us to assess the role of Wnt pathway in K-to-DVB. By testing
lin-17, beta-catenins and
pop-1 mutants, we found that indeed the Wnt pathway is involved. In
lin-17(Ø), ACD is prevented and K.p displays an epithelial phenotype with big nucleus, expression of epithelial markers and absence of neuronal markers. In addition, we found that an important role of Wnt activity is to turn on expression of the
lim-6 terminal selector in K.p. Finally, we found that Wnt and the reprogramming factor
sem-4 act through two different pathways. These results demonstrate that during natural transdifferentiation the presence of an asymmetric cell division is not enough to allow cell identity change, but reprogramming factors are required in parallel to confer cell plasticity.