Abstract
Purpose :
Apert syndrome is caused by missense point mutations of fibroblast growth factor receptor 2 (FGFR2) and is associated with craniofacial bone anomalies and strabismus1. The aim of this project is to better understand the contribution of abnormal FGFR2 signaling intrinsic to the extraocular muscles (EOM) in Apert syndrome by characterizing EOM in mouse models of Apert syndrome that express the Apert FGFR2 point mutation in muscle stem cells (MuSC) or in muscle.
Methods :
Litters were produced by crossing Apert FGFR2 (+/S252Wflox)2 mice with either Pax7-Cre (JAX #010530) which express the Cre recombinase driven by the Pax7 promoter to express the Apert FGFR2 mutation in MuSC (Pax7 AS mutants) or with alpha human skeletal actin (HSA or Acta1)-Cre (JAX #006149) which expresses Cre recombinase driven by the muscle specific ACTA1 promoter to express the FGFR2 mutation in muscle (HSA AS mutants). EOM were harvested at postnatal age of 3 weeks, flash frozen, and sectioned using a cryostat. Hematoxylin and eosin (H&E) staining was used to compare EOM from scleral insertion to the posterior orbit between mutant and littermate controls. Analysis for each muscle was done on the cross-sectional area (CSA) and thickness averaged across the muscle length as well as on the largest CSA and thickness.
Results :
The orbital and global layers of lateral rectus (LR) and superior rectus (SR) of Pax7 AS mutants are significantly smaller in both the largest and average CSA and thickness when compared to wildtype. Additionally, Pax7 AS mutant mice are significantly smaller, weighing about 56% of the wildtype littermates’ body weight. In contrast, HSA AS mutants appear to have similar LR size and body weights to wildtype littermates.
Conclusions :
Pax7 AS mutants are significantly smaller with smaller EOM compared to wildtype, while HSA AS mutants are similar in body weight and EOM size compared to wildtype. Abnormally sustained FGF signaling in MuSC may be altering MuSC proliferation and/or differentiation in EOM, leading to abnormal EOM size in LR and SR. This will aid in establishing targets for the development of innovative therapies that could specifically address the abnormal FGFR2 signaling seen in strabismus in Apert syndrome patients.
1Khong JJ, et al. Am J Ophthalmol. 2006;142(2):328-330.
2Wang Y, et al. Development. 2005;132(15):3537-3548.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.