ZFIN ID: ZDB-PUB-180921-1
Ca2+ concentration-dependent premature death of igfbp5a-/- fish reveals a critical role of IGF signaling in adaptive epithelial growth.
Liu, C., Xin, Y., Bai, Y., Lewin, G., He, G., Mai, K., Duan, C.
Date: 2018
Source: Science signaling   11(548): (Journal)
Registered Authors: Duan, Cunming
Keywords: none
MeSH Terms:
  • Animals
  • Animals, Genetically Modified
  • Calcium/metabolism*
  • Cell Line, Tumor
  • Cell Proliferation/genetics
  • Epithelial Cells/cytology
  • Epithelial Cells/metabolism*
  • Humans
  • Insulin-Like Growth Factor Binding Protein 5/genetics
  • Insulin-Like Growth Factor Binding Protein 5/metabolism*
  • Mice
  • Mutation
  • Signal Transduction*
  • Somatomedins/metabolism*
  • Zebrafish/genetics
  • Zebrafish/growth & development
  • Zebrafish/metabolism*
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism*
PubMed: 30228225 Full text @ Sci. Signal.
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ABSTRACT
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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