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Development 128, 2049-2062 (2001)
© 2001 The Company of Biologists Limited

Differential contributions of AF-1 and AF-2 activities to the developmental functions of RXR{alpha}

Bénédicte Mascrez, Manuel Mark, Wojciech Krezel, Valérie Dupé, Marianne LeMeur, Norbert B. Ghyselinck and Pierre Chambon*

Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS-INSERM-ULP-Collège de France, BP163, 67404 Illkirch Cedex, C.U. de Strasbourg, France

*Author for correspondence (e-mail: chambon{at}igbmc.u-strasbg.fr)

Accepted March 8, 2001

We have engineered a mouse mutation that specifically deletes most of the RXR{alpha} N-terminal A/B region, which includes the activation function AF-1 and several phosphorylation sites. The homozygous mutants (RXR{alpha}af1o), as well as compound mutants that further lack RXRß and RXR{gamma}, are viable and display a subset of the abnormalities previously described in RXR{alpha}-null mutants. In contrast, RXR{alpha}af1o/RAR-/-({alpha}, ß or {gamma}) 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 RXR{alpha} 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/RXR{alpha} 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 RXR{alpha}, ß and {gamma} appear to be dispensable, suggesting that RXRs act as silent heterodimeric partners in this process. However, AF-2 of RXR{alpha}, but not AF-1, is required for differentiation of labyrinthine trophoblast cells, a late step in the formation of the placental barrier.

Key words: Nuclear receptor, Retinoic acid, Gene knockout, Transcriptional activity, Activation function, Placenta, Limb, Mouse




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