The nutritional status of an organism can greatly impact the function and behavior of stem and progenitor cells . However, the regulatory circuits that inform these cells about the dietary environment remain to be elucidated. Newly hatched C. Elegans larvae (L1s) halt development in "L1 arrest" or "L1 diapause" until ample food is encountered and triggers stem and progenitor cells to exit from quiescence . The insulin/insulin-like growth factor signaling (IIS) pathway plays a key role in this reactivation [3, 4], but its site(s) of action have not been elucidated nor have the nutrient molecule(s) that stimulate the pathway been identified. By tissue-specifically modulating the activity of its components, we demonstrate that the IIS pathway acts in the hypodermis to regulate nutrition-responsive reactivation of neural and mesodermal progenitor cells. We identify ethanol, a likely component of the natural Caenorhabditis habitat, and amino acids as nutrients that synergistically reactivate somatic progenitor cells and upregulate expression of insulin-like genes in starved L1 larvae. The hypodermis likely senses the availability of amino acids because forced activation of the amino-acid-responsive Rag-TORC1 (target of rapamycin complex 1) pathway in this tissue can also release somatic progenitor cell quiescence in the presence of ethanol. Finally, there appears to be crosstalk between the IIS and Rag-TORC1 pathways because constitutive activation of the IIS pathway requires Rag to promote reactivation. This work demonstrates that ethanol and amino acids act as dietary cues via the IIS and Rag-TORC1 pathways in the hypodermis to coordinately control progenitor cell behavior.
Bibliographical noteFunding Information:
We thank Drs. A. Fire, O. Hobert, T. Inoue, Y. Jin, Y. Kohara, M. Maduro, S. Mitani, and S. Strome for reagents and strains. Some C. elegans strains used in this study were provided by the Caenorhabditis Genetics Center, which is supported by the NIH—Office of Research Infrastructure Programs (P40 OD010440), and the Mitani lab, which is funded through the National Bio-Resource Project of the Ministry of Education, Culture, Sports, Science and Technology (MEXT). Supported by Japan Society for the Promotion of Science KAKENHI grant numbers 23229001 (T.K.) and 23370083 (K.K.), MEXT KAKENHI grant numbers 24657081 (T.K.) and 23116703 (M.F.), the National Science Foundation (IOB-0515682; A.E.R.), and American Heart Association Midwest Affiliate (AHA no. 0520074Z; M.F.).