Dr. Susan Motch Perrine interviewed by Disease Models & Mechanisms following publication of "Mandibular dysmorphology due to abnormal embryonic osteogensis in FGFR2-related craniosynostosis mice"

Dr. Susan Motch Perrine of the Penn State Richtsmeier lab and Dr. Meng Wu of Mt. Sinai were recently interviewed for a first person perspective in Disease Models & Mechanisms ( http://dmm.biologists.org/content/12/5/dmm040568?fbclid=IwAR1HNKXkZOrZqvreeYBTLIzpLehCEvTHvR2waWWT0nOV3HSLJvjg3MDN2U4 ) following publication of their article, "Mandibular dysmorphology due to abnormal embryonic osteogensis in FGFR2-related craniosynostosis mice" (http://dmm.biologists.org/content/12/5/dmm038513?ijkey=1d417f5469d89e9859d2a5cc88d52816547cff96&keytype2=tf_ipsecsha). Dr. Perrine was also awarded the journal cover for this issue (http://dmm.biologists.org/content/12/5.cover-expansion?fbclid=IwAR3uuHxX0W7qrz5YYOKXQSdUDTWV9zFFS7_JqdESZ-iPoSaQeMzV4m_OqAY). 

Using three mouse models of Apert, Crouzon and Pfeiffer craniosynostosis syndromes, the researchers examined how embryonic development of the mandible is affected by fibroblast growth factor receptor 2 (Fgfr2) mutations. Quantitative analysis of skeletal form at birth revealed differences in mandibular morphology between mice carrying an Fgfr2 mutation and their unaffected littermates. Murine embryos carrying one of two mutations causative for Apert syndrome showed an increase in the size of the osteogenic anlagen and Meckel's cartilage (MC), in addition to changes in the microarchitecture and mineralization of the developing mandible. The mechanism for mandibular dysgenesis in the Apert Fgfr2+/S252W mouse resulting in the most severe phenotypic effects was further analyzed in detail and found to occur to a lesser degree in the other craniosynostosis mouse models. Laser capture microdissection and RNA-seq analysis revealed transcriptomicc changes in mandibular bone at embryonic day 16.5 (E16.5), highlighting increased expression of genes related to osteoclast differentiation and dysregulated genes active in bone mineralization. Increased osteoclastic activity was corroborated by TRAP assay and in situ hybridization of Csf1r and Itgb3. Upregulated expression of Enpp1 and Ank was validated in the embryos and found to result in elevated inorganic pyrophosphate concentration. Increased proliferation of osteoblast in the mandible and chondrocytes forming MC was identified in Fgfr2+/S252W embryos at E12.5. These findings provide evidence that FGFR2 gain-of-function mutations differentially affect cartilage formation and intramembranous ossification of dermal bone, contributing to mandibular dysmorphogenesis in craniosynostosis syndromes.