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An alternatively spliced fibroblast growth factor (FGF)-5 mRNA is abundant in brain and translates into a partial
1Biosignaling Department, National Institute of Bioscience and Human Technology, Tsukuba, Ibaraki 305-8566, Japan.
Abstract:
We detected in the brain and then cloned two novel, short forms of human and mouse fibroblast growth factor (FGF)-5 mRNA, which were designated human FGF-5S (hFGF-5S) and mouse FGF-5S (mFGF-5S), respectively. Genomic analysis indicated that mFGF-5S and authentic mFGF-5 mRNAs were transcribed from a single gene; hFGF-5S and mFGF-5S mRNAs were generated by excluding the second exon of the respective FGF-5 genes, and the alternatively spliced mRNAs encoded for 123- and 121-amino acid proteins, respectively. Indeed, a neuron-like cell line expressing mFGF-5S mRNA secreted a protein of the expected size and with FGF-5 antigenicity. In PC12 cells, expression of hFGF-5 or exposure to hFGF-5 protein induced differentiation. Neither expression of hFGF-5S, alone, nor co-expression of hFGF-5S with hFGF-5 induced significant differentiation. At high concentrations, hFGF-5S protein partially antagonized FGF-5 activity, whereas by itself, hFGF-5S exerted very weak neurotrophic activity. hFGF-5S protein binds to FGF receptor (FGFR)-1 on PC12 transfectants and partially inhibits hFGF-5-induced tyrosine phosphorylation of FGFR-1 and an FGFR substrate, but it also induces phosphorylation by itself. These results suggest that FGF-5S is a naturally expressed partial agonist/antagonist of FGF-5 neurotrophic activity in the brain and that its effects are exerted in part at the level of the receptor.
Insights
Researchers discovered novel short forms of fibroblast growth factor (FGF)-5 mRNA in the brain. These FGF-5S variants act as partial agonists/antagonists, modulating FGF-5 neurotrophic activity at the receptor level.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Fibroblast growth factor (FGF)-5 is a key regulator of neurotrophic activity in the brain.
- Alternative splicing of mRNA transcripts can lead to the production of protein isoforms with distinct functions.
Purpose of the Study:
- To identify and characterize novel short forms of human and mouse FGF-5 mRNA.
- To investigate the functional role of these short FGF-5 variants in neuronal differentiation and signaling.
Main Methods:
- Cloning of novel FGF-5 mRNA variants (hFGF-5S and mFGF-5S) from brain tissue.
- Genomic analysis to determine gene transcription and alternative splicing mechanisms.
- Expression studies in neuron-like cell lines (PC12) to assess protein secretion and functional activity.
- Analysis of FGF receptor (FGFR)-1 binding and downstream signaling pathways (tyrosine phosphorylation).
Main Results:
- Two novel short forms, hFGF-5S and mFGF-5S, were identified and cloned.
- These variants are generated by excluding the second exon of the FGF-5 gene, encoding shorter proteins (123 and 121 amino acids).
- hFGF-5S protein exhibits partial antagonism of FGF-5 activity and weak neurotrophic effects, binding to FGFR-1 and modulating its phosphorylation.
Conclusions:
- FGF-5S represents a naturally expressed molecule that acts as a partial agonist/antagonist of FGF-5 neurotrophic activity.
- The observed effects of FGF-5S are mediated, at least in part, through interactions with FGF receptors.
- These findings reveal a new layer of regulation in FGF-5 signaling within the brain.