Embryonic Survival and Severity of Cardiac and Craniofacial Defects Are Affected by Genetic Background in Fibroblast Growth Factor-16 Null Mice

Abstract

Disruption of the X-chromosome fibroblast growth factor 16 (Fgf-16) gene, a member of the FGF-9 subfamily with FGF-20, was linked with an effect on cardiac development in two independent studies. However, poor trabeculation with lethality by embryonic day (E) 11.5 was associated with only one, involving maintenance in Black Swiss (Bsw) versus C57BL/6 mice. The aim of this study was to examine the potential influence of genetic background through breeding the null mutation onto an alternate (C57BL/6) background. After three generations, 25% of Fgf-16(-/Y) mice survived to adulthood, which could be reversed by reducing the contribution of the C57BL/6 genetic background by back crossing to another strain. There was no significant difference between FGF-9 and FGF-20 RNA levels in Fgf-16 null versus wild-type mice regardless of strain. However, FGF-8 RNA levels were reduced significantly in Bsw but not C57BL/6 mice. FGF-8 is linked to anterior heart development and like the FGF-9 subfamily is reportedly expressed at E10.5. Like FGF-16, neuregulin as well as signaling via ErbB2 and ErbB4 receptors have been linked to trabeculae formation and cardiac development around E10.5. Basal neuregulin, ErbB2, and ErbB4 as well as FGF-8, FGF-9, and FGF-16 RNA levels varied in Bsw versus C57BL/6 mice. These data are consistent with the ability of genetic background to modify the phenotype and affect embryonic survival in Fgf-16 null mice.

A novel method, the Variant Impact On Linkage Effect Test (VIOLET), leads to improved identification of causal variants in linkage regions

“…Mouse strain-dependent variability supports such lack of overlap. [39][40][41][42][43] Indeed, fibronectin defects cause cardiovascular malformations; 44 but there is substantial phenotypic …”

Heart-specific expression of FGF-16 and a potential role in postnatal cardioprotection

“…In contrast, FGF-16 null mice on a C57BL/6 mouse strain genetic background through disruption of exons 2 and 3, survive fetal development [21]. There is, however, a significant decrease in embryonic cardiac myocyte proliferation, which is consistent with a role for FGF-16 during embryonic heart development [21,27]. Heart weight and cardiac myocyte number was also decreased at six months of age after birth [21].…”

“…These effects are visible at E10.5 but more pronounced at E11.5, and a decrease in FGF-8 RNA levels was also noted [22]. FGF-8 is linked to anterior heart development and is expressed at E10.5 [27]. In contrast, FGF-16 null mice on a C57BL/6 mouse strain genetic background through disruption of exons 2 and 3, survive fetal development [21].…”

“…FGF-16 is also associated with the FGF signaling network acting downstream of Wnt/b-catenin pathway that is involved in the expansion of anterior heart field Isl1 (+) cardiovascular progenitor cells, from which cardiac myocytes are derived [26]. Loss of FGF-16 in Black Swiss null mice via disruption of exon 1 results in embryonic lethality as well as evidence of cardiac and skeletal or craniofacial defects as early as day 11.5 [27]. The former includes chamber dilation, thinning of the atrial and ventricular walls, and poor trabeculation.…”

The FGF Family in Humans, Mice, and Zebrafish: Development, Physiology, and Pathophysiology

“…Fgf16 knockout mice on a C57BL/6 genetic background are viable, but have impaired embryonic cardiomyocyte proliferation (Hotta et al, 2008). Fgf16 knockout phenotypes may be more severe on a Black Swiss genetic background where they die at embryonic day (E) 10.5 with severely impaired cardiac and facial development (Lu et al, 2008;Lu et al, 2010). Fgf17 and Fgf22 knockout mice are viable, but show impaired hindbrain development and impaired synaptic differentiation, respectively (Xu et al, 2000;Terauchi et al, 2010).…”