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. 2008 Aug 22;373(2):270-4.
doi: 10.1016/j.bbrc.2008.06.029. Epub 2008 Jun 17.

FGF-16 is required for embryonic heart development

Shun Yan Lu  1 , Farah Sheikh, Patricia C Sheppard, Agnes Fresnoza, Mary Lynn Duckworth, Karen A Detillieux, Peter A Cattini
Affiliations

FGF-16 is required for embryonic heart development

Shun Yan Lu et al. Biochem Biophys Res Commun. .

Abstract

Fibroblast growth factor 16 (FGF-16) expression has previously been detected in mouse heart at mid-gestation in the endocardium and epicardium, suggesting a role in embryonic heart development. More specifically, exogenously applied FGF-16 has been shown to stimulate growth of embryonic myocardial cells in tissue explants. We have generated mice lacking FGF-16 by targeting the Fgf16 locus on the X chromosome. Elimination of Fgf16 expression resulted in embryonic death as early as day 11.5 (E11.5). External abnormalities, including hemorrhage in the heart and ventral body region as well as facial defects, began to appear in null embryos from E11.5. Morphological analysis of FGF-16 null hearts revealed cardiac defects including chamber dilation, thinning of the atrial and ventricular walls, and poor trabeculation, which were visible at E10.5 and more pronounced at E11.5. These findings indicate FGF-16 is required for embryonic heart development in mid-gestation through its positive effect on myocardial growth.

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Figures

Fig. 1
Fig. 1
Generation of FGF-16 null mice by homologous recombination. (A) Schematic of Fgf16 targeting construct, showing the replacement of Fgf16 exon 1 (Ex 1) with the lacZ/neo cassette and introduction of a new KpnI site as shown. Maps of the relative genomic region of wild-type Fgf16 locus (top), the targeting locus (center), and the locus after recombination (bottom) are shown. Positions are numbered along the murine X-chromosome relative to first KpnI restriction site upstream of Fgf16 exon 1. The location of the probe used for DNA blot analysis in panel B is indicated, as are the positions of the PCR primers (shown by arrows) used in genotyping in panel C. (B) Genomic DNA from hemizygous (−/Y) Fgf16 null embryos (E12.5), as well as heterozygous female (+/−) and wild-type male (+/Y) littermates was digested with Acc65I (an isoschizomer of KpnI). The probe detected a 14.2 kb fragment in the wild-type (+/Y), a 7.7 kb fragment in null mice (−/Y), and both fragments in heterozygous females (+/−). (C) Genotyping of embryos by PCR. Primers to detect the recombinant (‘knockout’) allele amplified a 207-bp fragment from the targeted locus. Primers to detect the Y-linked Sry gene amplified a 211-bp fragment. The corresponding genotypes are shown below the image.
Fig. 2
Fig. 2
RT-PCR analysis of Fgf16 expression in wild-type and Fgf16 null embryos. (A) RNA from the head (Hd, including the otic vesicle and olfactory placode), pharyngeal arches (Ph) and heart (Ht) of both wild-type (+/Y) and Fgf16 null (−/Y) E9.5 embryos were isolated and analyzed by RT-PCR using primers for FGF-16 and GAPDH as indicated. (B) Similar RT-PCR analysis in E10.5 embryos, with the addition of RNA from tails (Ta).
Fig. 3
Fig. 3
Gross morphology of embryonic development in Fgf16 null mice. Wild-type (WT, +/Y) and Fgf16 null (Nu, −/Y) embryos at E10.5, E11.5, and E12.5 are shown. (A) At E10.5, the null embryo is indistinguishable from its wild-type littermate. (B) For E11.5, right (top) and left (bottom) views of the same representative wild-type and null embryos are shown. Note that at this time point, some Fgf16 null embryos exhibited no differences from their age-matched wild-type counterparts. (C) At E12.5, the phenotype of all Fgf16 null embryos is represented by the figure. Affected embryos at E11.5 and all Fgf16 null embryos at E12.5 display hemorrhage in and around the cardiac and the ventral body regions, as well as marked craniofacial defects.
Fig. 4
Fig. 4
Histological assessment of heart defects in FGF-16 null mice. Mid-level cross-sections from E10.5 and E11.5 mouse embryos were stained by Hematoxylin and Eosin. (A) At E10.5, sections from two different null (Nu) embryos show an enlarged common ventricle (CV) and compromised trabeculation (tr) compared with a wild-type (WT) littermate. (B) At E11.5, both atrial and ventricular chamber enlargement are observed in null embryos (Nu) compared to WT. The changes to the trabeculation are now more pronounced, especially in the bulbus cordis (bc), which will become the future right ventricle. The arrow heads indicate thinning of the ventricular and atrial walls compared to WT. Other abbreviations: CA, common atrium; LA, left atrium.
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