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

We have engineered a mouse mutation that specifically deletes the C-termina l 18 amino acid sequence of the RXR alpha protein, This deletion correspond s to the last helical a 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-dependen t transactivation by RXR alpha. The homozygous mutants (RXR alpha af2(0)), which die during the late fetal period or at birth, exhibit a subset of the abnormalities previously observed in RXR alpha(-/-) mutants, often with in complete penetrance. In marked contrast, RXR alpha af2(0)/RXR beta(-/-) and RXR alpha af2(0)/RXR beta(-/-)/RXR gamma(-/-) compound mutants display a l arge array of malformations, which nearly recapitulate the full spectrum of the defects that characterize the fetal vitamin A-deficiency (VAD) syndrom e and were previously found in RAR single and compound mutants, as well as in RXR alpha/RAR(alpha, beta or gamma) compound mutants. Analysis of RXR al pha af2(0)/RAR(alpha, beta or gamma) compound mutants also revealed that th ey exhibit many of the defects observed in the corresponding RXR alpha/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 ligand-dependent transactivation i s instrumental in retinoid signalling during development.