Orphan Receptor DAX-1 Is a Shuttling RNA Binding Protein Associated with Polyribosomes via mRNA

Abstract

The DAX-1 (NR0B1) gene encodes an unusual member of the nuclear hormone receptor superfamily which acts as a transcriptional repressor. Mutations in the human DAX-1 gene cause X-linked adrenal hypoplasia congenita (AHC) associated with hypogonadotropic hypogonadism (HHG). We have studied the intracellular localization of the DAX-1 protein in human adrenal cortex and mouse Leydig tumor cells and found it to be both nuclear and cytoplasmic. A significant proportion of DAX-1 is associated with polyribosomes and is found complexed with polyadenylated RNA. DAX-1 directly binds to RNA, two domains within the protein being responsible for cooperative binding activity and specificity. Mutations in DAX-1 found in AHC-HHG patients significantly impair RNA binding. These findings reveal that DAX-1 plays multiple regulatory roles at the transcriptional and posttranscriptional levels.

ACKNOWLEDGMENTS

We thank J.-P. Renaud for critical reading of the manuscript; B. Bardoni, J.-P. Renaud, E. Puvion, F. Puvion, J.-L. Vonesch, N. Messaddeq, M.-P. Gaub, G. Lesa, and A. Ziemiecki for discussions, help, and gifts of reagents; and E. Heitz, M. Rastegar, J.-L. Weickert, I. Kolb-Cheynel, P. Eberling, and the IGBMC oligonucleotide synthesis, sequencing, and cell culture services for technical help.

K. Ohe is supported by a postdoctoral fellowship from the Fondation de la Recherche Médicale. This study was funded by grants from Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Centre Hospitalier Universitaire Régional, Fondation de la Recherche Médicale, and Association pour la Recherche sur le Cancer.