Insulin signaling promotes germline proliferation in C. elegans.
Cell proliferation must be coordinated with cell fate specification during development, yet interactions among pathways that control these two critical aspects of development are not well understood. The coordination of cell fate specification and proliferation is particularly crucial during early germline development, when it impacts the establishment of stem/progenitor cell populations and ultimately the production of gametes. In C. elegans, insulin/IGF-like receptor (IIR) signaling has been implicated in fertility, but the basis for the fertility defect had not been previously characterized. We found that IIR signaling is required for robust larval germline proliferation, separate from its well-characterized role in preventing dauer entry. IIR signaling stimulates the larval germline cell cycle. This activity is distinct from Notch signaling, occurs in a predominantly germline-autonomous manner, and responds to somatic activity of ins-3 and ins-33, genes that encode putative insulin-like ligands. IIR signaling in this role acts through the canonical PI3K pathway, inhibiting DAF-16/FOXO. However, signaling from these ligands does not inhibit daf-16 in neurons nor in the intestine, two tissues previously implicated in other IIR roles. Our data are consistent with a model in which: (1) under replete reproductive conditions, the larval germline responds to insulin signaling to ensure robust germline proliferation that builds up the germline stem cell population; and (2) distinct insulin-like ligands contribute to different phenotypes by acting on IIR signaling in different tissues.
Michaelson
David
D
Developmental Genetics Program, Helen and Martin Kimmel Center for Stem Cell Biology, Skirball Institute of Biomolecular Medicine, Department of Pathology, New York University School of Medicine, New York, NY 10016, USA.
Korta
Dorota Z
DZ
Capua
Yossi
Y
Hubbard
E Jane Albert
EJ
D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans / Q000196:embryology* / Q000235:genetics / Q000254:growth & development / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D005260:Female; D051858:Forkhead Transcription Factors; D017238:Genes, Helminth; D005854:Germ Cells / Q000166:cytology / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D007814:Larva / Q000166:cytology / Q000378:metabolism; D008024:Ligands; D008297:Male; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism; D017451:Receptors, Somatomedin / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
D029742:Caenorhabditis elegans Proteins; D016207:Cytokines; D051858:Forkhead Transcription Factors; C507325:Ins-33 protein, C elegans; D007328:Insulin; D008024:Ligands; D051880:Receptors, Notch; D017451:Receptors, Somatomedin; D014157:Transcription Factors; C108831:daf-16 protein, C elegans; D019869:Phosphatidylinositol 3-Kinases; C107483:DAF-2 protein, C elegans; D011972:Receptor, Insulin