Journal
JOURNAL OF CELL SCIENCE
Volume 124, Issue 16, Pages 2723-2734Publisher
COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.084699
Keywords
Retinoic acid; Cyp26b1; Skeletogenesis; Limb development; Chondroblast differentiation; Hypertrophy; Chondrogenic programme
Categories
Funding
- Skeletal Regenerative Medicine Canadian Institutes of Health (CIHR)
- Canadian Arthritis Network
- Michael Smith Foundation for Health Research
- CIHR
- Arthritis Society
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Cyp26b1, a retinoic acid (RA)-metabolising enzyme, is expressed in the developing limb bud, and Cyp26b1(-/-) mice present with severe limb defects. These malformations might be attributable to an RA-induced patterning defect; however, recent reports suggest that RA is dispensable for limb patterning. In this study, we examined the role of endogenous retinoid signalling in skeletogenesis using Cyp26b1(-/-) mice and transgenic mice in which Cyp26b1 is conditionally deleted under control of the Prrx1 promoter beginning at similar to E9.5 (Prrx1Cre(+)/Cyp26b1(fl/fl)). We found that the limb phenotype in Prrx1Cre+/Cyp26b1(fl/fl) mice was less severe than that observed in Cyp26b1(-/-) animals and that a change in retinoid signalling contributed to the difference in phenotypes. We systematically examined the role of endogenous RA signalling in chondrogenesis and found that Cyp26b1(-/-) cells and limb mesenchymal cells treated with a CYP inhibitor, are maintained in a pre-chondrogenic state, exhibit reduced chondroblast differentiation and have modestly accelerated chondrocyte hypertrophy. Furthermore, Cyp26b1(-/-) mesenchyme exhibited an increase in expression of genes in a closely related tendogenic lineage, indicating that retinoid signals in the limb interfere with differentiation and maintain progenitor status. Together, these findings support an important function for RA in regulating the behaviour of mesenchymal progenitors, and their subsequent differentiation and maturation.
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