Ca2+concentration–dependent premature death ofigfbp5a−/−fish reveals a critical role of IGF signaling in adaptive epithelial growth
The phenotype gap is a challenge for genetically dissecting redundant endocrine signaling pathways, such as the six isoforms in the insulin-like growth factor binding protein (IGFBP) family. Although overexpressed IGFBPs can inhibit or potentiate IGF actions or have IGF-independent actions, mutant mice lacking IGFBP-encoding genes do not exhibit major phenotypes. We found that although zebrafish deficient inigfbp5adid not show overt phenotypes when raised in Ca2+-rich solutions, they died prematurely in low Ca2+conditions. A group of epithelial cells expressingigfbp5atake up Ca2+and proliferate under low Ca2+conditions because of activation of IGF signaling. Deletion ofigfbp5ablunted low Ca2+stress–induced IGF signaling and impaired adaptive proliferation. Reintroducing zebrafish Igfbp5a, but not its ligand binding–deficient mutant, restored adaptive proliferation. Similarly, adaptive proliferation was restored in zebrafish lackingigfbp5aby expression of human IGFBP5, but not two cancer-associated IGFBP5 mutants. Knockdown of IGFBP5 in human colon carcinoma cells resulted in reduced IGF-stimulated cell proliferation. These results reveal a conserved mechanism by which a locally expressed Igfbp regulates organismal Ca2+homeostasis and survival by activating IGF signaling in epithelial cells and promoting their proliferation in Ca2+-deficient states. These findings underscore the importance of physiological context when analyzing loss-of-function phenotypes of endocrine factors.