Generation and analysis of a mouse model of a lethal dwarfism, Thanatophoric Dysplasia type II. T. Iwata1, L. Chen2, C. Li2, C.A. Francomano1, C. Deng2. 1) NHGRI/NIH, Bethesda, MD; 2) NIDDK/NIH, Bethesda, MD.
Thanatophoric Dysplasia type II (TDII) is a common form of neonatal lethal dwarfism associated with a specific mutation, Lys650Glu, in fibroblast growth factor receptor 3 (FGFR3). Recently, several mouse models have been generated with Fgfr3 mutations that showed the phenotype of achondroplasia, a milder form of dwarfism. TDII pathophysiology, on the other hand, is more severe and involves earlier embryonic bone development and dominant inheritance. We have successfully generated a TDII mouse model using an in vivo cre-lox recombination strategy to overcome the lethal effect associated with the Lys650Glu mutation. Upon cre-mediated recombination, the mutant mice are designed to have an exact chromosomal organization as wild type animals except for the introduced point mutation. Mutant pups heterozygous for the dominant mutation showed reduced skeletal growth and neonatal death, a phenotype closely resembling that in humans. Detailed analysis of the embryonic skeleton revealed abnormal rib cage development, which may be the cause of neonatal lethality. We also found that macrocephaly was caused by abnormal growth of the brain prior to skull bone formation at E11.5, suggesting a hitherto unknown role of Fgfr3 in early brain development. Furthermore, delayed knee joint formation was observed in mutant pups as early as E12.5, indicating the involvement of Fgf signaling in early knee joint formation. Finally, we observed increased proliferation and delayed differentiation in mutant growth plate chondrocytes. Neither the expression of the PTHrP receptor nor that of Ihh were altered, while the expression of patched, a downstream signaling component, was induced in the mutant growth plate, suggesting a new regulatory mechanism of embryonic bone development by Fgfr3. In summary, the TDII mouse closely mimics human dysplasia and will be useful for clinical studies. Our current studies at both the morphological and molecular levels will provide insights into the mechanisms of TDII pathology and the roles of Fgfr3 in the early development of bone and other tissues.