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Objective: To generate knockin mice that express a tamoxifen-inducible Cre recombinase from the Prg4 locus (Prg4(GFPCreERt2) mice) and to use these animals to fate-map the progeny of Prg4-positive articular cartilage cells at various ages., Methods: We crossed Prg4(GFPCreERt2) mice with Rosa26(floxlacZ) or Rosa26(mTmG) reporter strains, admin-istered tamoxifen to the double heterozygous offspring at different ages, and assayed Cre-mediated recom-bination by histochemistry and/or fluorescence microscopy., Results: In 1-month-old mice, the expression of the Prg4(GFPCreERt2) allele mirrored the expression of endogenous Prg4 and, when tamoxifen was admin-istered for 10 days, caused Cre-mediated recombination in ∼70% of the superficial-most chondrocytes. Prg4(GFPCreERt2)-expressing cells were mostly confined to the top 3 cell layers of the articular cartilage in 1-month-old mice, but descendants of these cells were located in deeper regions of the articular cartilage in aged mice. On embryonic day 17.5, Prg4(GFPCreERt2)-expressing cells were largely restricted to the superficial-most cell layer of the forming joint, yet at ∼1 year, the progeny of these cells spanned the depth of the articular cartilage., Conclusion: Our results suggest that Prg4-expressing cells located at the joint surface in the embryo serve as a progenitor population for all deeper layers of the mature articular cartilage. Also, our findings indicate that Prg4(GFPCreERt2) is expressed by superficial chondrocytes in young mice, but expands into deeper regions of the articular cartilage as the animals age. The Prg4(GFPCreERt2) allele should be a useful tool for inducing efficient Cre-mediated recombination of loxP-flanked alleles at sites of Prg4 expression., (© 2015, American College of Rheumatology.)