Ca²⁺ concentration-dependent premature death of igfbp5a 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 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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