We have engineered a mouse mutation that specifically deletes most of the RXRα N-terminal A/B region, which includes the activation function AF-1 and several phosphorylation sites. The homozygous mutants (RXRαaf1o), as well as compound mutants that further lack RXRβ and RXRγ, are viable and display a subset of the abnormalities previously described in RXRα-null mutants. In contrast, RXRαaf1o/RAR−/−(α, β or γ) compound mutants die in utero and exhibit a large array of malformations that nearly recapitulate the full spectrum of the defects that characterize the fetal vitamin A-deficiency (VAD) syndrome. Altogether, these observations indicate that the RXRα AF-1 region A/B is functionally important, although less so than the ligand-dependent activation function AF-2, for efficiently transducing the retinoid signal through RAR/RXRα heterodimers during embryonic development. Moreover, it has a unique role in retinoic acid-dependent involution of the interdigital mesenchyme. During early placentogenesis, both the AF-1 and AF-2 activities of RXRα, β and γ appear to be dispensable, suggesting that RXRs act as silent heterodimeric partners in this process. However, AF-2 of RXRα, but not AF-1, is required for differentiation of labyrinthine trophoblast cells, a late step in the formation of the placental barrier.

Keywords:
Nuclear receptor, Retinoic acid, Gene knockout, Transcriptional activity, Activation function, Placenta, Limb, Mouse
© 2001.
2001
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