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Review
. 2020 Dec 31;22(1):390.
doi: 10.3390/ijms22010390.

What Can We Learn from FGF-2 Isoform-Specific Mouse Mutants? Differential Insights into FGF-2 Physiology In Vivo

Friederike Freiin von Hövel  1   2 , Ekaterini Kefalakes  1   2 , Claudia Grothe  1   2
Affiliations
Review

What Can We Learn from FGF-2 Isoform-Specific Mouse Mutants? Differential Insights into FGF-2 Physiology In Vivo

Friederike Freiin von Hövel et al. Int J Mol Sci. .

Abstract

Fibroblast growth factor 2 (FGF-2), ubiquitously expressed in humans and mice, is functionally involved in cell growth, migration and maturation in vitro and in vivo. Based on the same mRNA, an 18-kilo Dalton (kDa) FGF-2 isoform named FGF-2 low molecular weight (FGF-2LMW) isoform is translated in humans and rodents. Additionally, two larger isoforms weighing 21 and 22 kDa also exist, summarized as the FGF-2 high molecular weight (FGF-2HMW) isoform. Meanwhile, the human FGF-2HMW comprises a 22, 23, 24 and 34 kDa protein. Independent studies verified a specific intracellular localization, mode of action and tissue-specific spatiotemporal expression of the FGF-2 isoforms, increasing the complexity of their physiological and pathophysiological roles. In order to analyze their spectrum of effects, FGF-2LMW knock out (ko) and FGF-2HMWko mice have been generated, as well as mice specifically overexpressing either FGF-2LMW or FGF-2HMW. So far, the development and functionality of the cardiovascular system, bone formation and regeneration as well as their impact on the central nervous system including disease models of neurodegeneration, have been examined. This review provides a summary of the studies characterizing the in vivo effects modulated by the FGF-2 isoforms and, thus, offers a comprehensive overview of its actions in the aforementioned organ systems.

Keywords: FGF-2HMWko; FGF-2HMWtg; FGF-2LMWko; FGF-2LMWtg; FGF-2ko; bone physiology; cardiovascular system; central nervous system; mutant mice.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Endogenous FGF-2 expression and generation of FGF-2 isoform-specific mice. (A), based on one mRNA, translation from different CUG codons results in a 22, 23, 24, and 34 kDa product in humans summarized as FGF-2HMW. Meanwhile only the 21 and 22 kDa protein are present in rodents. Additionally, translation initiated at the AUG codon leads to expression of the 18 kDa FGF-2 isoform indicated as FGF-2LMW. (B), FGF-2 isoform-specific ko mice were created by gene targeting resulting in FGF-2HMWko mice, only expressing FGF-2LMW and vice versa FGF-2LMWko mice which only possess FGF-2HMW. These mice were more closely characterized with regard to development of the central nervous system and effects in neurodegenerative disease models as well as development and functionality of the cardiovascular system, bone formation and regeneration (indicated by square brackets). (C), Also FGF-2 isoform-specific tg mice were generated, which overexpress specific FGF-2 isoforms in addition to endogenous FGF-2. With regard to the cardiovascular system FGF-2HMWtg mice overexpressing the human 24 kDa FGF-2 isoform driven by the PGK were analyzed as well as FGF-2LMWtg mice overexpressing the rat FGF-2LMW protein using the RSV promoter. In opposition to that, bone physiology was characterized in FGF-2HMWtg mice additional possessing the human 22, 23, and 24 kDa FGF-2 isoform using the Col3.6 promoter, which also drives human FGF-2LMW isoform expression in FGF-2LMWtg mice. Col3.6, collagen 3.6 promoter; FGF-2, fibroblast growth factor 2; H, human; HMW, high molecular weight; kDA, kilo Dalton; ko, knock out; LWW, low molecular weight; PKC, protein kinase C; R, rat; RSV, Rous sarcoma virus long terminal repeat; tg, transgenic.
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