Non-autonomous insulin signaling regulates the duration of mitosis inC. elegansgermline stem and progenitor cells

Abstract

AbstractStem and progenitor cell mitosis is essential for tissue development and homeostasis. How these cells ensure proper chromosome segregation, and thereby maintain mitotic fidelity, in the complex physiological environment of a living animal is poorly understood. Here we usein situlive-cell imaging ofC. elegansgermline stem and progenitor cells (GSPCs) to ask whether signaling pathways that play a conserved role in regulating stem and progenitor cell cycle progression also impact mitosis. Through a candidate screen we identify a new role for the insulin/IGF receptor (IGFR),daf-2,as a regulator of GSPC mitosis. Mitosis is delayed indaf-2/IGFR mutants, and these delays require canonical, DAF-2/IGFR to DAF-16/FoxO insulin signaling, here acting cell non-autonomously from the soma. We further show that while mitotic delays indaf-2/IGFR mutants depend on the spindle assembly checkpoint, they are not accompanied by a loss of mitotic fidelity. Finally, we show that caloric restriction, which delays GSPC mitosis and compromises mitotic fidelity, does not act via the canonical insulin signaling pathway, and instead requires AMP-activated kinase (AMPK). Together this work demonstrates that GSPC mitosis is regulated by at least two genetically separable signaling pathways and highlights the importance of signaling networks for proper stem and progenitor cell mitosisin vivo.Author SummaryStem and progenitor cells drive tissue development and sustain adult tissue turnover by producing new daughter cells via cell division and the success of cell division relies on proper chromosome segregation during mitosis. Stem and progenitor cells perform mitosis in the complex environment of a living animal, yet relatively little is known about how events during mitosis are influenced by thisin vivocontext. Here we took advantage of the germline stem and progenitor cells of the model nematodeC. elegansto ask whether signaling pathways that coordinate stem and progenitor cell division with external cues also play a role during mitosis. We uncovered a role for the insulin signaling pathway in regulating mitosis in these cells. Reduced insulin signaling delays germline stem and progenitor cell mitosis without compromising chromosome segregation and acts non-autonomously from somatic tissues. While insulin signaling is known to link cell division with nutritional status in many species, we found that it did not mediate the effects of caloric restriction on germline stem and progenitor cell mitosis. Instead, caloric restriction acts via the conserved energy-sensing regulator AMPK. These results uncover new regulators of germline stem and progenitor cell mitosis and emphasize the importance of signaling pathways for proper stem and progenitor cell mitosisin vivo.