Non-autonomous PMK-1/p38 MAPK signaling ensures homeostatic downregulation of germline stem cell proliferation in C. elegans

Stem cell underproliferation leads to tissue loss while over proliferation favors hyperplasia and tumorigenesis. Stem and progenitor proliferation rates are therefore usually coupled to the needs for their differentiated cellular progenies in the tissue(s) they serve. We used the C. elegans hermaphrodite reproductive system to understand how germline stem cell (GSC) proliferation is linked to sperm availability and oocyte usage. We developed a forward genetic screening method to identify genes required for the homeostatic downregulation of GSC proliferation when oocytes are not used, where germline homeostasis defective ( ghd ) mutants grow benign differentiated germline tumors. We provide evidence that the TIR-1/SARM1 metabolic sensor works together with the NIPI-3/TRIB1 pseudokinase to activate a canonical PMK-1/p38 MAPK signaling cascade in the somatic gonad, shut down the extracellular regulated kinase MPK-1/ERK, and couple GSC proliferation to oocyte needs. Similar multi-tissue signaling modules could underlie homeostatic stem cell regulation and prevent benign tumorigenesis in humans.