Keeping it together: the role of FGF signaling in embryonic ventral wall closure

Authors

• MGS Boylan
• M Anderson
• I Hung
• D Ornitz
• M Lewandoski

Abstract

Omphalocele is a severe ventral wall (VW) defect in which the abdominal contents have herniated through an enlarged umbilical ring during embryonic development. In humans, omphalocele is associated with increased mortality, but the etiology of this condition is poorly understood. We serendipitously observed omphalocele after generating mice in which the genes coding for the FGF8 subfamily (Fgf8, Fgf17 and Fgf18) were inactivated specifically in the primitive streak and emerging mesoderm using TCre. We examined the contribution of each of the three genes to the penetrance of the phenotype and determined a genetic hierarchy (Fgf18>Fgf8>Fgf17). Omphalocele is thought to be caused by defective myoblast migration from the somites, leading to a failure in VW closure. Fgf8 subfamily null embryos also show impaired myoblast migration, suggesting the defect we observe is analogous to omphalocele in humans. Experiments using different Cre lines show that the Fgf8 subfamily is dispensable in the muscles themselves and may be required in the presomitic mesoderm (PSM) or somites. The role of Fgf8 in the PSM has been well studied, but any roles of Fgf17 and Fgf18 have not been previously identified. We observed ectopic cell death in the somites of Fgf8 subfamily mutants, which could explain the defects in the ventral muscles. To test whether the cell death observed contributes to the VW defect, we additionally knocked out the pro-apoptotic genes, Bak and Bax. We found that the incidence of omphalocele dropped significantly when apoptosis is suppressed genetically, suggesting that the observed somitic cell death causes omphalocele. We are currently investigating whether the somite specification program is malfunctional; we are also examining the role of FGF receptors 1 and 2 in VW closure. This project will clarify the role of FGF signaling in VW formation, which has received little attention despite its medical relevance.

Scientific Focus Area: Developmental Biology

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