DAX-1/NR0B1 is an unusual orphan receptor that has a pivotal role in the development and function of steroidogenic tissues and of the reproductive axis. Recent studies have also indicated that this transcription factor has an important function in stem cell biology and in several types of cancer. Here I critically review the most important findings on the role of DAX-1 in development, physiology, and disease of endocrine tissues since the cloning of its gene twenty years ago. 1. Introduction Nuclear hormone receptors are intracellular proteins that are responsible for sensing lipophilic substances and mediating their physiological actions, directly regulating the expression of target genes through binding to DNA. Nuclear receptors are implicated in a large variety of biological processes and have a special importance in development and endocrine functions (reviewed in [1]). A common feature of the members of this protein family is the presence of a conserved domain in the carboxyterminal part of the protein, which has the capacity to bind ligands (ligand-binding domain: LBD) modulating the transcriptional activity of the receptor and which folds as an antiparallel alpha-helical sandwich [2]. However, ligands are not known for all family members: the terminology of “orphan” is then used to indicate those proteins, which often possess a defined transcriptional function in the apparent absence of ligands. This spotlight paper is focused on a peculiar orphan receptor, DAX-1 (NR0B1 in the nuclear receptor official nomenclature), and will review the most important findings about its role in development, physiology, and disease. 2. Cloning and Structure of DAX-1: An Unusual Orphan Receptor Cloning of the DAX-1 gene dates back to 1994. Previous studies by Bardoni and colleagues described a specific disorder of sex development, causing male-to-female phenotypic sex reversal (dosage-sensitive sex (DSS) reversal) in individuals bearing a normal SRY gene, associated with duplication of a minimal region spanning approximately 160？kb in chromosome Xp21 [3]. Cloning of expressed sequences in this region led to the identification of a two-exon gene encoding a novel member of the nuclear receptor family [4]. Remarkably, deletions, frameshift, missense, and stop mutations in this gene were found in patients affected with adrenal hypoplasia congenita (AHC), a congenital disorder characterized by impaired development of the adrenal cortex that can lead to adrenal insufficiency and is associated with hypogonadotropic hypogonadism (HHG) after puberty [4, 5]. Given its
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