Abstract
Many cell types display the remarkable ability to alter their cellular phenotype in response to specific external or internal signals. Such phenotypic plasticity is apparent in the nematode Caenorhabditis elegans when adverse environmental conditions trigger entry into the dauer diapause stage. This entry is accompanied by structural, molecular, and functional remodeling of a number of distinct tissue types of the animal, including its nervous system. The transcription factor (TF) effectors of 3 different hormonal signaling systems, the insulin-responsive DAF-16/FoxO TF, the TGFβ-responsive DAF-3/SMAD TF, and the steroid nuclear hormone receptor, DAF-12/VDR, a homolog of the vitamin D receptor (VDR), were previously shown to be required for entering the dauer arrest stage, but their cellular and temporal focus of action for the underlying cellular remodeling processes remained incompletely understood. Through the generation of conditional alleles that allowed us to spatially and temporally control gene activity, we show here that all 3 TFs are not only required to initiate tissue remodeling upon entry into the dauer stage, as shown before, but are also continuously required to maintain the remodeled state. We show that DAF-3/SMAD is required in sensory neurons to promote and then maintain animal-wide tissue remodeling events. In contrast, DAF-16/FoxO or DAF-12/VDR act cell-autonomously to control anatomical, molecular, and behavioral remodeling events in specific cell types. Intriguingly, we also uncover non-cell autonomous function of DAF-16/FoxO and DAF-12/VDR in nervous system remodeling, indicating the presence of several insulin-dependent interorgan signaling axes. Our findings provide novel perspectives into how hormonal systems control tissue remodeling.
Highlights
We found that tagging each of the transcription factor (TF) loci had no detectable effect on gene function in the context of dauer formation, as assessed by crossing the tagged loci into distinct Daf-c mutant backgrounds, whose Daf-c phenotype is known to be suppressed by reduction of daf-3/SMAD, daf-12/vitamin D receptor (VDR), or daf-16/FoxO gene function
By shifting the dauers initially grown in control conditions onto auxin-containing plates, we found that DAF-16/FoxO is continuously required to maintain inx-6 expression during dauer arrest (Fig 6A), which is consistent with the continuous requirement for DAF-16/FoxO to retain animals in the dauer stage, as described above (Fig 3C and 3D)
By auxin-shifting the dauers initially grown in control conditions, we find that the DAF-16/FoxO requirement in the gut is continuous, since removal of DAF-16/FoxO in the intestine post-dauer entry still results in derepression of pharyngeal pumping (Fig 9H and 9I)
Summary
The identity of a fully differentiated cell in a multicellular organism is usually described by a number of phenotypic criteria, ranging from overall anatomy to cellular function to molecular. The ability of postmitotic, differentiated cells to remodel a number of their anatomical, molecular, and functional features during dauer entry in mid-larval development (and their ensuing reversibility upon dauer exit) is a remarkable example of the plasticity of the cellular phenotype. How are these remodeling events superimposed onto the regulatory state of a differentiated neuron? Tissue- and cell type–specific removal of each of these TFs reveals complex requirements for these systems and shows that one hormonal axis acts mostly cell-autonomously, while two others act in both target cells (i.e., cell-autonomously), and act outside the remodeled organ Such cell nonautonomous activities reveal a number of interorgan signaling axes, from the nervous system to the gut and muscle and from the gut to the nervous system. We show that in the context of the nervous system these hormonal signaling systems cooperate with hardwired terminal selector-type TFs that provide the cellular specificity and potential for remodeling
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