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Published on: January 4, 2018
Local reduction of organ size in transgenic mice expressing a soluble insulin-like growth factor
S Zaina1, R V Newton, M R Paul
1Department of Zoology, University of Oxford, United Kingdom. silvio.zaina@medforsk.mas.lu.se
Abstract:
Genetic evidence suggests that the insulin-like growth factor II (IGF-II)/mannose-6-phosphate receptor (IGF2R) slows growth. A soluble form of IGF2R (sIGF2R) is produced by proteolytic cleavage of the intact cellular receptor and is found at high levels in fetal and neonatal plasma. To test the hypothesis that sIGF2R modulates organ size in vivo, we generated transgenic mice expressing a mouse Igf2r complementary DNA in which the transmembrane domain sequence was deleted. The transgene was driven by the keratin-10 promoter and was expressed at the highest levels in the skin and alimentary canal. Transgenics showed disproportionately reduced size of the alimentary canal, where the wet weight was decreased by 9-20% and the dry weight was decreased by 20-30%, whereas the water content per unit dry weight was not significantly changed. In addition, the circulating levels of IGF-II and the latent form of transforming growth factor-beta1 were increased by 58-77% and 56-140%, respectively, whereas plasma epidermal growth factor levels showed a 24-35% reduction. The serum and tissue activities of four lysosomal enzymes were not affected, with the exception of the colon in the line expressing the transgene at highest levels, where enzyme activities were decreased compared with control values. These results support a significant role for the sIGF2R in local modulation of organ size in vivo.
Insights
Soluble insulin-like growth factor II/mannose-6-phosphate receptor (sIGF2R) significantly reduces alimentary canal size in transgenic mice. This suggests sIGF2R plays a key role in modulating organ size in vivo.
Area of Science:
- Molecular Biology
- Developmental Biology
- Genetics
Background:
- Genetic evidence indicates the insulin-like growth factor II (IGF-II)/mannose-6-phosphate receptor (IGF2R) inhibits growth.
- A soluble form, sIGF2R, is generated by receptor cleavage and is abundant in fetal and neonatal plasma.
Purpose of the Study:
- To investigate the in vivo role of sIGF2R in modulating organ size.
- To test the hypothesis that sIGF2R influences organ size.
Main Methods:
- Generation of transgenic mice expressing a truncated mouse Igf2r cDNA lacking the transmembrane domain.
- Expression driven by the keratin-10 promoter, targeting skin and alimentary canal.
- Analysis of organ size, circulating growth factors, and lysosomal enzyme activities.
Main Results:
- Transgenic mice exhibited a disproportionately reduced size of the alimentary canal (9-20% wet weight, 20-30% dry weight reduction).
- Circulating IGF-II and latent transforming growth factor-beta1 levels increased, while plasma epidermal growth factor levels decreased.
- Lysosomal enzyme activities were largely unaffected, except for a decrease in the colon of high-expressing lines.
Conclusions:
- The results support a significant role for soluble IGF2R in the local regulation of organ size.
- sIGF2R acts as a modulator of organ size, particularly within the alimentary canal.
