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Overexpression of fra-2 in transgenic mice perturbs normal eye development
J Z McHenry1, A Leon, K I Matthaei
1Division of Immunology and Cell Biology, John Curtin School of Medical Research, Australian National University, Camberra ACT.
Abstract:
The major components of transcription factor AP-1 (Activator Protein 1) are encoded by the two families of genes related to the proto-oncogenes c-fos and c-jun. The fos-related antigen-2 (fra-2) gene is the most recently described member of the Fos family. To determine the oncogenic potential of fra-2, transgenic mice were generated which over-express fra-2 in a number of tissues. No tumours were evident in any transgenic mice up to 18 months of age, although eye development was severely disrupted in these animals. Corneal abnormalities could be observed histologically as early as embryonic day 15.5 and eyelid fusion failed to occur. Adult eyes were characterized by generalized anterior segment dysgenesis similar to that previously reported in transgenic mice over-expressing transforming growth factor alpha (TGF alpha), and occasionally microphthalmia. Expression of fra-2 was shown to increase following TGF alpha treatment of cells in vitro, suggesting that AP-1 complexes containing Fra-2 contribute to TGF alpha signalling events.
Insights
Overexpression of the fos-related antigen-2 (fra-2) gene in transgenic mice disrupted eye development, causing corneal abnormalities and anterior segment dysgenesis. This suggests fra-2 plays a role in TGF alpha signaling, but not oncogenesis.
Area of Science:
- Molecular Biology
- Developmental Biology
- Oncogenesis
Background:
- Transcription factor AP-1 (Activator Protein 1) is crucial in cellular processes.
- The c-fos and c-jun gene families encode AP-1 components.
- Fos-related antigen-2 (fra-2) is a recently identified member of the Fos gene family.
Purpose of the Study:
- To investigate the oncogenic potential of the fra-2 gene.
- To understand the role of fra-2 in tissue development.
Main Methods:
- Generation of transgenic mice over-expressing fra-2.
- Histological analysis of tissues from transgenic mice.
- In vitro cell culture to study fra-2 expression following TGF alpha treatment.
Main Results:
- Transgenic mice over-expressing fra-2 showed no tumor development up to 18 months.
- Severe disruption of eye development, including corneal abnormalities and failed eyelid fusion, was observed.
- Adult eyes exhibited anterior segment dysgenesis and occasional microphthalmia.
- fra-2 expression increased after TGF alpha treatment in vitro.
Conclusions:
- Fra-2 overexpression does not appear to possess oncogenic potential.
- Fra-2 is critical for normal eye development.
- Fra-2 may be involved in transforming growth factor alpha (TGF alpha) signaling pathways.