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Abnormal bone growth and selective translational regulation in basic fibroblast growth factor (FGF-2) transgenic mice
J D Coffin1, R Z Florkiewicz, J Neumann
1Department of Cell Biology, Scripps Research Institute, La Jolla, CA 92121, USA.
Abstract:
Basic fibroblast growth factor (FGF-2) is a pleiotropic growth factor detected in many different cells and tissues. Normally synthesized at low levels, FGF-2 is elevated in various pathologies, most notably in cancer and injury repair. To investigate the effects of elevated FGF-2, the human full-length cDNA was expressed in transgenic mice under control of a phosphoglycerate kinase promoter. Overexpression of FGF-2 caused a variety of skeletal malformations including shortening and flattening of long bones and moderate macrocephaly. Comparison by Western blot of FGF-2 transgenic mice to nontransgenic littermates showed expression of human FGF-2 protein in all major organs and tissues examined including brain, heart, lung, liver, kidney, spleen, and skeletal muscle; however, different molar ratios of FGF-2 protein isoforms were observed between different organs and tissues. Some tissues preferentially synthesize larger isoforms of FGF-2 while other tissues produce predominantly smaller 18-kDa FGF-2. Translation of the high molecular weight isoforms initiates from unconventional CUG codons and translation of the 18-kDa isoform initiates from an AUG codon in the FGF-2 mRNA. Thus the Western blot data from the FGF-2 transgenic mice suggest that tissue-specific expression of FGF-2 isoforms is regulated translationally.
Insights
Elevated basic fibroblast growth factor (FGF-2) in transgenic mice caused skeletal malformations. Tissue-specific FGF-2 protein isoforms are regulated by translational control mechanisms.
Area of Science:
- Molecular Biology
- Genetics
- Developmental Biology
Background:
- Basic fibroblast growth factor (FGF-2) is a key growth factor with diverse cellular roles.
- Elevated FGF-2 levels are associated with pathologies like cancer and injury repair.
- Understanding FGF-2's function requires investigating the impact of its overexpression.
Purpose of the Study:
- To investigate the effects of elevated basic fibroblast growth factor (FGF-2) expression.
- To analyze the tissue-specific expression and regulation of FGF-2 protein isoforms.
Main Methods:
- Generation of transgenic mice expressing human full-length FGF-2 cDNA under a phosphoglycerate kinase promoter.
- Analysis of skeletal morphology in FGF-2 transgenic mice and nontransgenic littermates.
- Western blot analysis to detect FGF-2 protein expression and isoform ratios across various organs and tissues.
Main Results:
- Overexpression of FGF-2 led to skeletal malformations, including shortened long bones and macrocephaly.
- Human FGF-2 protein was detected in all major organs and tissues of transgenic mice.
- Distinct molar ratios of FGF-2 protein isoforms (larger isoforms and 18-kDa FGF-2) were observed in different tissues.
Conclusions:
- Tissue-specific expression of FGF-2 isoforms is regulated at the translational level.
- Alternative translation initiation from CUG and AUG codons generates different FGF-2 isoforms.
- FGF-2 overexpression can induce significant developmental abnormalities, particularly in the skeletal system.