Conditional mutation of fibroblast growth factor receptors 1 and 2 results in an omphalocele in mice associated with disruptions in ventral body wall muscle formation

Abstract

Background/Purpose We observed that fibroblast growth factor receptors 1 and 2 (Fgfr1, Fgfr2) are expressed during abdominal wall development in mice and hypothesized that conditional mutation of these genes would result in abdomial wall defects. Methods Section in situ hybridizations were performed for Fgfr1 and Fgfr2 on wild-type embryos at embryonic day (E) 11.5 and E13.5. Conditional mutation of Fgfr1 and Fgfr2 was achieved with a tamoxifen inducible Cre at E8.5. Litters were harvested at E17.5, whole mount photographs were taken, and paraffin sections were generated and stained with hematoxylin and eosin. Results Fgfr1 was expressed in ectoderm, lateral plate mesoderm, and myoblasts, whereas Fgfr2 was expressed almost exclusively in the early dermis and ectoderm of the abdominal wall. Conditional mutation of both Fgfr2 alleles and one Fgfr1 allele resulted in omphalocele in 38.7% of mutants. Histologic examination in mutants demonstrated disruptions in dermal and muscle development. Conclusions Mutant embryos with omphalocele arising from mutation in Fgfr1 and Fgfr2 exhibit disruptions in the development of the secondary abdominal wall structures. These findings are consistent with a model of ventral abdominal wall development in which organization of the muscles and connective tissue (secondary abdominal wall structures) is influenced by positional information emanating from the primary abdominal wall.

Crucial requirement of ERK/MAPK signaling in respiratory tract development

“…The phenotypes resulting from the mesenchymal ablation of Mek genes were anticipated due to the large spectrum of actions of the ligands trafficking via the ERK/MAPK pathway. For instance, abnormal body wall formation and omphalocele were reported in mice carrying conditional mutations in both Fgfr1 and Fgfr2 genes (Nichol et al, 2011). Normal lung growth requires adequate space in the thoracic cavity and appropriate tonic and cyclic distending forces originating in part from fetal breathing movements (Kotecha, 2000).…”

A review of genetic factors underlying craniorachischisis and omphalocele: Inspired by a unique trisomy 18 case

“…Research in humans and mouse models also demonstrated a correlation of many SNPs with NTDs while anterior closure defects genes are less studied for these genes. Similarly, Nichol et al () pinpoints the FGFR1 and FGFR2 genes in OMP formation, but no other literature suggests a link to NTDs. These phenotypes may result from unrelated genetic phenomena or co‐occur as part of the vast interconnected genetic puzzle.…”

Registry analysis supports different mechanisms for gastroschisis and omphalocele within shared developmental fields

“…). Genes so far defined by omphalocele syndromes are probably those effecting pattern transformation (e.g., fibroblast growth factor receptors, Nichol et al, ; filamin A in Melnick‐Needles syndrome, Foley et al, ) rather than pattern genesis, as for the few genes associated with gastroschisis susceptibility [Snelling and Davies, ], including the cell adhesion molecule, atrial natriuretic peptide, and nitric oxide synthase 3 noted by Torfs et al []. The molecules involved in establishing A‐P and D‐V gradients in the 3‐week embryo, the earliest contributors to AWD, would be present in the oriented egg cytoplasm and, by analogy to fly genes [Nüsslein‐Volhard et al, ], may exhibit maternal genetic effect [Wilson, ].…”