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Molecular and cellular characterization of the CYP26b1-null limb phenotype

University of British Columbia

Cyp26b1, a retinoic acid (RA)-metabolizing enzyme, is expressed in the developing limb bud and Cyp26b1-/- mice present with severe early limb defects characterized by truncated skeletal elements and oligodactyly. These malformations have previously been attributed to a 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 ~E9.5 (Prrx1Cre⁺/Cyp26b1fl/fl). We found that the limb phenotype in Prrx1Cre⁺/Cyp26b1fl/fl mice was less severe than Cyp26b1-/- animals and that a difference in retinoid signalling contributed to the difference in phenotypes. We systematically examined the role of RA signalling in chondrogenesis and found that Cyp26b1-/- cells are maintained at a pre-chondrogenic stage, exhibit reduced chondroblast differentiation, and exhibit a modest impact on chondrocyte hypertrophy. Furthermore, Cyp26b1-/- mesenchyme exhibited an increase in the expression of Scleraxis and other tendon markers, indicating that increased retinoid signalling in the limb maintains the ability of precursor cells to commit to other mesenchymal lineages. We conclude that RA signalling negatively impacts chondrogenesis before the onset of Ihh signalling, and has a positive impact on chondrocyte hypertrophy. This suggests that the limb phenotype in Cyp26b1-/- animals results from defects in the execution of a patterning program, and not so much in the patterning program itself.

Text

2011-05-31

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/29719

Cell and Developmental Biology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/