The Interaction of Genetic Background and Mutational Effects in Regulation of Mouse Craniofacial Shape

Abstract

Inbred genetic background significantly influences the expression of phenotypes associated with known genetic perturbations and can underlie variation in disease severity between individuals with the same mutation. However, the effect of epistatic interactions on the development of complex traits, such as craniofacial morphology, is poorly understood. Here, we investigated the effect of three inbred backgrounds (129X1/SvJ, C57BL/6J, and FVB/NJ) on the expression of craniofacial dysmorphology in mice (Mus musculus) with loss of function in three members of the Sprouty family of growth factor negative regulators (Spry1, Spry2, or Spry4) in order to explore the impact of epistatic interactions on skull morphology. We found that the interaction of inbred background and the Sprouty genotype explains as much craniofacial shape variation as the Sprouty genotype alone. The most severely affected genotypes display a relatively short and wide skull, a rounded cranial vault, and a more highly angled inferior profile. Our results suggest that the FVB background is more resilient to Sprouty loss of function than either C57 or 129, and that Spry4 loss is generally less severe than loss of Spry1 or Spry2. While the specific modifier genes responsible for these significant background effects remain unknown, our results highlight the value of intercrossing mice of multiple inbred backgrounds to identify the genes and developmental interactions that modulate the severity of craniofacial dysmorphology. Our quantitative results represent an important first step toward elucidating genetic interactions underlying variation in robustness to known genetic perturbations in mice.

Downregulation of FGF Signaling by Spry4 Overexpression Leads to Shape Impairment, Enamel Irregularities, and Delayed Signaling Center Formation in the Mouse Molar

“…Their expression is induced upon growth factor stimulation, and the protein products inhibit FGFR‐mediated activation of the ERK‐MAPK signaling pathway . In the mouse, Spry2 and Spry4 prevent the development of supernumerary teeth, and Spry1 , Spry2 , and Spry4 are required for correct molar cusp patterning . In the mouse incisor, which is a continuously growing tooth, Spry2 and Spry4 restrict the differentiation of enamel‐secreting ameloblasts to the labial side, allowing asymmetric enamel deposition …”

“…(17) In the mouse, Spry2 and Spry4 prevent the development of supernumerary teeth, (7) and Spry1, Spry2, and Spry4 are required for correct molar cusp patterning. (18,19) In the mouse incisor, which is a continuously growing tooth, Spry2 and Spry4 restrict the differentiation of enamel-secreting ameloblasts to the labial side, allowing asymmetric enamel deposition. (20) Here, to further investigate the roles of the FGF signaling pathway in odontogenesis, we utilized a transgenic mouse line (K14-Spry4) in which the expression of mouse Spry4 is driven in the epithelium of many ectodermal organs under the control of the human keratin-14 promoter.…”

Gpr63is a novel modifier of microcephaly inTtc21bmouse mutants

“…To increase the frequency of craniofacial phenotypes to facilitate future molecular analyses, the Ttc21b aln allele was serially backcrossed onto the C57BL/6J (B6) strain. The B6 genetic background has previously shown to be more susceptible to craniofacial phenotypes in a number of studies (Hide et al 2002;Dixon and Dixon 2004;Mukhopadhyay et al 2012;Percival et al 2017). As the Ttc21b aln was serially backcrossed to the B6 background, we noticed the relative size of the forebrain tissues in B6.Cg-Ttc21b aln/aln mutants increased substantially, although they remained smaller than control brains and still lacked olfactory bulbs ( Fig.1 E,F).…”

Developmental processes regulate craniofacial variation in disease and evolution

“…In particular, the FVB/NJ background was found to be more robust to Sprouty mutations than either 129X1/SvJ or C57BL/6J. This study also revealed that modifier genes can also change the direction of the effect, as the same loss of function mutation in Spry1 caused opposite effects on craniofacial shape in two different inbred backgrounds (Percival et al, ). Finally, pleiotropy modifiers determine the number of features that are affected by a mutation.…”