Fgf8 dosage regulates jaw shape and symmetry through pharyngeal‐cardiac tissue relationships

Abstract

Background: Asymmetries in craniofacial anomalies are commonly observed. In the facial skeleton, the left side is more commonly and/or severely affected than the right. Such asymmetries complicate treatment options. Mechanisms underlying variation in disease severity between individuals as well as within individuals (asymmetries) are still relatively unknown.Results: Developmental reductions in fibroblast growth factor 8 (Fgf8) have a dosage dependent effect on jaw size, shape, and symmetry. Further, Fgf8 mutants have directionally asymmetric jaws with the left side being more affected than the right. Defects in lower jaw development begin with disruption to Meckel's cartilage, which is discontinuous. All skeletal elements associated with the proximal condensation are dysmorphic, exemplified by a malformed and misoriented malleus. At later stages, Fgf8 mutants exhibit syngnathia, which falls into two broad categories: bony fusion of the maxillary and mandibular alveolar ridges and zygomatico-mandibular fusion. All of these morphological defects exhibit both inter-and intra-specimen variation. Conclusions: We hypothesize that these asymmetries are linked to heart development resulting in higher levels of Fgf8 on the right side of the face, which may buffer the right side to developmental perturbations. This mouse model may facilitate future investigations of mechanisms underlying human syngnathia and facial asymmetry.

Fgf8regulates first pharyngeal arch segmentation through pouch-cleft interactions

“…Quantification of Fgf8 mRNA levels in E10.5 heads indicates that mice heterozygous for the Neo allele ( Fgf8 Neo/+ ) express 90% of Fgf8 (wildtype; WT) levels, mice heterozygous for the Delta allele ( Fgf8 Δ/+ ) express 60% of WT levels, mice homozygous for the Neo allele ( Fgf8 Neo/Neo ) express 35% of WT levels, and compound mutants ( Fgf8 Δ/Neo ) express 20% of WT levels (Green et al ., 2017). These mice and embryos were genotyped as previously reported (Green et al ., 2017; Meyers et al ., 1998; Zbasnik et al ., 2022). Embryos were collected and staged based on the number of days after the observation of a postcoital plug at E0.5.…”

“…We previously described how Fgf8 has a dosage effect on jaw size. Specifically, reductions in Fgf8 expression below about 40% of WT expression levels result in truncated and dysmorphic lower jaws (Green et al, 2017;Zbasnik et al, 2022). Mild mutants (which was not certified by peer review) is the author/funder.…”

“…The copyright holder for this preprint this version posted March 15, 2023. ; https://doi.org/10.1101/2023.03.15.532781 doi: bioRxiv preprint (Fgf8 Neo/Neo ; expressing 35% of Fgf8 relative to WT) exhibit minor truncations of the proximal mandible whereas more severe mutants (Fgf8 Δ/Neo ; expressing 20% of Fgf8 relative to WT) exhibit unilateral fusion of the upper and lower jaws (Zbasnik et al, 2022). Importantly, these defects are associated with malformations of PA1 epithelia which fail to separate the first and second arches.…”

Discordant growth of nasal cartilage and bone contributes to phenotypic variability of the skull in a mouse model

“…However, the path from genotype to phenotype is realized through developmental processes that encompass mechanisms at the molecular, cellular, and tissue levels 5 . While this nonlinear relationship between genotype and craniofacial phenotype appears to be common, few studies have looked at the specific developmental processes that underlie this nonlinearity 6,7 . In this study, we address this gap in knowledge by investigating the potential tissue‐level developmental determinants of a nonlinear relationship between genotype and skull phenotype using a mouse model.…”

Fgf8 regulates first pharyngeal arch segmentation through pouch-cleft interactions

“…Specifically, reductions in Fgf8 expression below about 40% of WT expression levels result in truncated and dysmorphic lower jaws ( Green et al, 2017 ; Zbasnik et al, 2022 ). Mild mutants ( Fgf8 Neo/Neo ; expressing 35% of Fgf8 relative to WT) exhibit minor truncations of the proximal mandible whereas more severe mutants ( Fgf8 Δ/Neo ; expressing 20% of Fgf8 relative to WT) exhibit unilateral fusion of the upper and lower jaws ( Zbasnik et al, 2022 ). Importantly, these defects are associated with malformations of PA1 epithelia which fail to separate the first and second arches.…”