PUBLICATION
Ca2+ concentration-dependent premature death of igfbp5a-/- fish reveals a critical role of IGF signaling in adaptive epithelial growth.
- Authors
- Liu, C., Xin, Y., Bai, Y., Lewin, G., He, G., Mai, K., Duan, C.
- ID
- ZDB-PUB-180921-1
- 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.
Citation
Liu, C., Xin, Y., Bai, Y., Lewin, G., He, G., Mai, K., Duan, C. (2018) Ca2+ concentration-dependent premature death of igfbp5a-/- fish reveals a critical role of IGF signaling in adaptive epithelial growth.. Science signaling. 11(548):.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping