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Human Molecular Genetics, 2000, Vol. 9, No. 11 1603-1613
© 2000 Oxford University Press

A neonatal lethal mutation in FGFR3 uncouples proliferation and differentiation of growth plate chondrocytes in embryos

Tomoko Iwata, Lin Chen1, Cui-ling Li1, Dmitry A. Ovchinnikov2, Richard R. Behringer2, Clair A. Francomano and Chu-Xia Deng1,+

Medical Genetics Branch, National Human Genome Research Institute and 1Genetics of Development and Disease Branch, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, 10/9N105, 10 Center Drive, Bethesda, MD 20892, USA and 2Department of Molecular Genetics, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA

We have generated the first mouse model of fibro­blast growth factor receptor 3 (Fgfr3) with the K644E mutation, which accurately reflects the embryonic onset of a neonatal lethal dwarfism, thanatophoric dysplasia type II (TDII). Long-bone abnormalities were identified as early as embryonic day 14, during initiation of endochondral ossification. Increased expression of Patched (Ptc) was observed, independent of unaltered expression of parathyroid hormone-related peptide (PTHrP) receptor and Indian Hedgehog (Ihh), suggesting a new regulatory role for Fgfr3 in embryos. We demonstrate that the mutation enhances chondrocyte proliferation during the early embryonic skeletal development, in contrast to previous reports that showed decreased proliferation in postnatal-onset dwarf mice with activating Fgfr3 mutations. This suggests that signaling through Fgfr3 both promotes and inhibits chondrocyte proliferation, depending on the time during development. In contrast, suppressed chondrocyte differentiation was observed throughout the embryonic stages, defining decreased differentiation as the primary cause of retarded longitudinal bone growth in TDII. This model was successfully crossed with a cartilage-specific Cre transgenic strain, excluding the lung as the primary cause of lethality.

+ To whom correspondence should be addressed. Tel: +1 301 402 7225; Fax: +1 301 480 1135; Email: chuxiad@bdg10.niddk.nih.gov


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