The molecular mechanisms that maintain cellular identities and prevent dedifferentiation or transdifferentiation remain mysterious. However, both processes are transiently used during animal regeneration. Therefore, organisms that regenerate their organs, appendages, or even their whole body offer a fruitful paradigm to investigate the regulation of cell fate stability. Here, we used Hydra as a model system and show that Zic4, whose expression is controlled by Wnt3/β-catenin signaling and the Sp5 transcription factor, plays a key role in tentacle formation and tentacle maintenance. Reducing Zic4 expression suffices to induce transdifferentiation of tentacle epithelial cells into foot epithelial cells. This switch requires the reentry of tentacle battery cells into the cell cycle without cell division and is accompanied by degeneration of nematocytes embedded in these cells. These results indicate that maintenance of cell fate by a Wnt-controlled mechanism is a key process both during homeostasis and during regeneration.
Living systems exhibit an unmatched complexity, due to countless and entangled interactions across scales. Here we aim to understand and gain control of a complex system, such as the segmentation timing of a developing mouse embryo, without a reference to these detailed interactions. To this end, we develop a coarse-grained approach in which theory guides the experimental identification of the system-level responses to entrainment, in the context of a network of coupled cellular oscillators that constitute the embryonic somite segmentation clock. We demonstrate period- and phase-locking of the embryonic system across a wide range of entrainment parameters, including higher-order coupling. These experimental quantifications allow to derive the phase response curve (PRC) and Arnold tongues of the system, revealing the essential dynamical properties of the embryonic segmentation clock. Our results indicate that at the macro-scale, the somite segmentation clock has characteristics of a highly non-linear oscillator close to a saddle-node on invariant cycle (SNIC) bifurcation and suggests the presence of long-term feedbacks. Combined, this coarse-grained theoretical-experimental approach reveals how we can derive simple, essential features of a highly complex dynamical system and hereby provides precise experimental control over the pace and rhythm of the somite segmentation clock.
The molecular mechanisms that maintain cell identities and prevent transdifferentiation remain mysterious. Interestingly, both dedifferentiation and transdifferentiation are transiently reshuffled during regeneration. Therefore, organisms that regenerate readily offer a fruitful paradigm to investigate the regulation of cell fate stability. Here, we used Hydra as a model system and show that Zic4 silencing is sufficient to induce transdifferentiation of tentacle into foot cells. We identified a Wnt-controlled Gene Regulatory Network that controls a transcriptional switch of cell identity. Furthermore, we show that this switch also controls the re-entry into the cell cycle. Our data indicate that maintenance of cell fate by a Wnt-controlled GRN is a key mechanism during both homeostasis and regeneration.
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