Abstract
TGF-beta signaling has a well established role not only in adult organ homeostasis but also in skeletal development. Follistatin-like 3 (FSTL3), related to follistatin, is an inhibitor of TGF-beta ligands, with an established role in glucose and fat metabolism. However it has not previously been studied in skeletal development. Using a FSTL3 knock-out (KO) mouse model we have studied both embryonic skeletal development and adult bone phenotypes. Staining for skeletal and cartilage markers during development shows acceleration of skeletal tissue differentiation, with an eventual normalization at E18.5 (which is just prior to birth). Acceleration of bone mineralization occurs during both endochondral and intramembranous ossification. Use of micro-CT imaging highlighted the development of a scoliosis in the KO animals, along with abnormal shape of cranium and cranial sutures. Further investigation of the cranial phenotype in adult KO mice reveals craniosynastosis, with atypical fusion of the frontal suture. These mice have a change in overall cranial shape with shortening of the anterior head and a compensatory expansion of the posterior cranial bones, in a similar fashion to brachyencephaly. Our study therefore highlights a significant role of FSTL3 in skeletal tissue development and mineralization, as well as the development of clinically significant skeletal developmental disorders such as scoliosis, craniosynastosis and brachyencephaly.
