The RXRα ligand-dependent activation function 2 (AF-2) is important for mouse development

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Abstract
We have engineered a mouse mutation that specifically deletes the C-terminal 18 amino acid sequence of the RXRα protein. This deletion corresponds to the last helical α structure (H12) of the ligand-binding domain (LBD), and includes the core of the Activating Domain of the Activation Function 2 (AF-2 AD core) that is thought to be crucial in mediating ligand-dependent transactivation by RXRα. The homozygous mutants (RXRαaf2o), which die during the late fetal period or at birth, exhibit a subset of the abnormalities previously observed in RXRα−/− mutants, often with incomplete penetrance. In marked contrast, RXRαaf2o/RXRβ−/− and RXRαaf2o/RXRβ−/−/RXRγ−/− compound mutants display a large array of malformations, which nearly recapitulate the full spectrum of the defects that characterize the fetal vitamin A-deficiency (VAD) syndrome and were previously found in RAR single and compound mutants, as well as in RXRα/RAR(α, β or γ) compound mutants. Analysis of RXRαaf2o/RAR(α, β or γ) compound mutants also revealed that they exhibit many of the defects observed in the corresponding RXRα/RAR compound mutants. Together, these results demonstrate the importance of the integrity of RXR AF-2 for the developmental functions mediated by RAR/RXR heterodimers, and hence suggest that RXR liganddependent transactivation is instrumental in retinoid signalling during development.