Research ArticlePhysiology

Ca2+ concentration–dependent premature death of igfbp5a−/− fish reveals a critical role of IGF signaling in adaptive epithelial growth

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Science Signaling  18 Sep 2018:
Vol. 11, Issue 548, eaat2231
DOI: 10.1126/scisignal.aat2231

Stressing out about low Ca2+

Under low Ca2+ conditions, an epithelial cell population in zebrafish known as NaR cells proliferate so that they can take up more Ca2+. Liu et al. found that Igf-binding protein 5A (Igfbp5a) was required for this adaptive proliferation and for survival under low Ca2+ conditions. The defect in NaR adaptive proliferation in igfbp5a−/− zebrafish was rescued by expression of wild-type human or zebrafish IGFBP5 but not two cancer-associated IGFBP5 mutants. Mice deficient in the various IGFBPs lack obvious phenotypes, and these results reveal the importance of using the appropriate physiological conditions to determine the function of IGFBPs.


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 in igfbp5a did not show overt phenotypes when raised in Ca2+-rich solutions, they died prematurely in low Ca2+ conditions. A group of epithelial cells expressing igfbp5a take up Ca2+ and proliferate under low Ca2+ conditions because of activation of IGF signaling. Deletion of igfbp5a blunted 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 lacking igfbp5a by 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.

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