Characterization of the Bent Bone Dysplasia Mouse: conditional knock‐in of FGFR2 M391R

Fibroblast Growth Factor Receptor 2 (FGFR2) regulates osteoprogenitor proliferation, self‐renewal and terminal differentiation during skeletal development, yet it remains unclear how the receptor distinctly elicits these cellular processes. We discovered a nuclear feature of FGF signaling that will elucidate with more specificity how FGFR2 regulates skeletal development. This mechanism emerged from our analysis of Bent Bone Dysplasia Syndrome (BBDS), an FGFR2‐disorder where the cell‐fate decisions of osteoprogenitor cells are biased towards self‐renewal over differentiation. We developed a mouse with a conditional knock‐in of the FGFR2 M391R mutation that causes BBDS in humans. DNA sequencing of cultured primary chondrocytes treated with Adeno‐GFP or Adeno‐Cre, confirmed efficient Cre‐mediated recombination of the knock‐in allele. Cell culture experiments and immunofluorescence further showed that the knock‐in FGFR2 M391R allele functions like that of BBDS, aberrantly translocating FGFR2 to the nucleus. Moreover, generation of a Wnt1‐Cre; FGFR2 M391R /+ mouse renders a phenotype, craniosynostosis, along with other defects in neural crest derived tissues, which strongly suggests that the mutation is dominant in mouse as it is in humans. Overall our preliminary data shows that the conditional knock‐in FGFR2 M391R mouse can be used to model human BBDS and can also be used to parse out the unknown endogenous and pathogenic functions of nuclear FGFR2. Support or Funding Information NIH RO1, NIH Diversity Supplement Award, and March of Dimes This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .