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Molecular Mechanisms of DAX1 Action Molecular Genetics and Metabolism 83 (2004) 60–73 www.elsevier.com/locate/ymgme Minireview Molecular mechanisms of DAX1 action Anita K. Iyera, Edward R.B. McCabea,b,c,d,e,¤ a Department of Human Genetics, David GeVen School of Medicine at UCLA, Los Angeles, CA, USA b Department of Pediatrics, David GeVen School of Medicine at UCLA, Los Angeles, CA, USA c UCLA Molecular Biology Institute, Los Angeles, CA, USA d Mattel Children’s Hospital at UCLA, Los Angeles, CA, USA e UCLA Center for Society, The Individual and Genetics, Los Angeles, CA, USA Received 25 May 2004; received in revised form 12 July 2004; accepted 13 July 2004 Abstract DAX1 (dosage sensitive sex reversal (DSS), adrenal hypoplasia congenita (AHC) critical region on the X chromosome, gene 1) encoded by the gene NR0B1, is an unusual orphan nuclear receptor that when mutated causes AHC with associated hypogonadotro- pic hypogonadism (HH), and when duplicated causes DSS. DAX1 expression has been shown in all regions of the hypothalamic– pituitary–adrenal–gonadal (HPAG) axis during development and in adult tissues, suggesting a critical role for DAX1 in the normal development and function of this axis. Steroidogenic factor 1 (SF1, NR5A1) knockout mice show similar developmental defects as AHC and HH patients, but paradoxically, DAX1 is a negative coregulator of SF1 transactivation. The function of DAX1 as an antagonist of SF1 in gonadal development is consistent with the fact that in humans, duplication of the region of the X chromosome containing DAX1 causes a similar phenotype as mutations in SF1. However, how disruption of DAX1 leads to adrenal, hypotha- lamic, and pituitary developmental defects similar to SF1 disruption remains to be clariWed. The exact mechanism of DAX1 action in each of these tissues during adulthood and critical stages of development are not fully understood. Recent evidence suggests a broader functional role for DAX1 as a negative coregulator of estrogen receptor (ER, NR3A1-2), liver receptor homologue-1 (LRH- 1, NR5A2), androgen receptor (AR, NR3C4), and progesterone receptor (PR, NR3C3), each by distinct repression mechanisms. DAX1 may have pleiotropic roles in addition to its function as a negative regulator of steroidogenesis during the development and adult function of the HPAG axis. 2004 Elsevier Inc. All rights reserved. Keywords: DAX1; NR0B1; Adrenal hypoplasia congenita; SF1; AR; ER; PR; LRH-1; Hypothalamic–pituitary–adrenal–gonadal axis; Nuclear receptor Introduction permanent zone that has normal structural zonation but is smaller than normal, with a minimal or absent fetal cor- Adrenal hypoplasia congenita (AHC) is an inherited tex. This form is generally associated with abnormal cen- disorder characterized by underdevelopment of the adre- tral nervous system and pituitary development and nal cortex [1]. It has an estimated frequency of 1:12,500 function, and is either sporadic or inherited in an autoso- live births and presents in two histological forms: the mal recessive manner. In the cytomegalic form of AHC, miniature adult and the cytomegalic forms. The adrenal associated with NR0B1 mutations, the permanent zone of glands of patients with the miniature adult form have a the cortex is absent or nearly absent, and the residual adrenal cortical tissue is structurally disorganized with large vacuolated cells that most closely resemble those in * Corresponding author. Fax: +1 310 206 4584. the fetal adrenal cortex, resulting in an adrenal cortex that E-mail address: [email protected] (E.R.B. McCabe). lacks normal postnatal zonation and is dysfunctional. 1096-7192/$ - see front matter 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.ymgme.2004.07.018 A.K. Iyer, E.R.B. McCabe / Molecular Genetics and Metabolism 83 (2004) 60–73 61 This form primarily aVects males as it is inherited in an X-linked manner. Patients with X-linked cytomegalic AHC present with adrenal insuYciency early in childhood, and exhibit salt- wasting, hypotension, hyperpigmentation, hyponatre- mia, hyperkalemia, hypoglycemia, decreased glucocorti- coid and aldosterone production, and increased levels of adrenocorticotropic hormone (ACTH) [1]. This disease is lethal without glucocorticoid and mineralocorticoid replacement therapy. Some patients with X-linked AHC who survive beyond childhood develop hypogonadotro- Fig. 1. Comparison of functional domain structure of members of the pic hypogonadism (HH), in which a mixed hypothalamic nuclear receptor superfamily (A) with DAX1 (B). and pituitary defect in the secretion of gonadotropins prevents normal puberty and requires treatment with most evolutionarily divergent and varies in size among testosterone for sexual maturity [1,2]. family members. It is considered a modulator domain X-linked AHC was originally mapped to Xp21 and and may contain a hormone independent transactivation the NR0B1 gene was subsequently identiWed by posi- domain (Activation Function 1 or AF-1). The C region is tional cloning as the causative agent of AHC, with muta- typically the most highly conserved and represents a tions or deletions in the NR0B1 gene identiWed in AHC DNA-binding domain (DBD) containing two zinc Wngers patients [3–5]. AHC can also present as part of an Xp21 that allow the receptor to recognize and bind hormone contiguous gene syndrome along with phenotypes of response elements in the promoters of target genes. The C glycerol kinase (GK) deWciency, Duchenne muscular region also contains receptor dimerization interfaces. The dystrophy (DMD), and mental retardation due to a D region serves as a hinge between the DBD and the large deletion encompassing NR0B1 and the neighbor- ligand-binding domain (LBD) and has been shown to ing GK and DMD loci [1]. AHC patients with defects in serve as a docking site for corepressors. The E region is the NR0B1 gene also develop HH, thus identifying the the second most highly conserved LBD, and mediates mutant DAX1 as the causative agent of both disorders ligand binding, dimerization, and nuclear localization. It [3–5]. DAX1 has also been shown to be involved in sex consists of 12 helices with an AF-2 hormone-dependent determination and gonadal development [6,7]. Male to transactivation domain in helix 12 that undergoes alloste- female sex reversal in XY individuals with an intact SRY ric conformational changes in response to ligand binding. gene was mapped to a 160 kb region of Xp21, which The DAX1 domain structure is rather unusual (Fig. includes NR0B1 [6]. Duplication of NR0B1, the gene 1B) [11,12]. The carboxy-terminal domain (CTD) is that encodes DAX1, in these sex reversed patients makes homologous to the LBD of other nuclear receptors and NR0B1 a very strong candidate for the dosage sensitive also contains an AF-2 transactivation domain, but sex reversal gene (DSS). DAX1 lacks the conventional DBD (Region C), modu- lator domain (Region A/B), and hinge region (Region D). Instead, the DAX1 amino-terminal domain (NTD) NROBI genomic organization and DAX1 protein domain has a novel structure consisting of 3.5 alanine/glycine structure rich repeats of a 65–70 amino acid motif that has no known homology to any other proteins, with the excep- NR0B1 has a very simple genomic structure with two tion of the related nuclear receptor superfamily member, exons separated by a single intron [3,5]. Exon 1 is small heterodimer partner (SHP), encoded by NR0B2 1168 base pairs (bp) in length, Exon 2 is 245 bp, and the [1]. The repeats show 33–70% identity to each other, and intron is 3385 bp [8]. The 1413 nucleotide cDNA also contain cysteine residues in conserved positions that encodes a 470 amino acid protein. Hossain et al. [9] have could potentially form zinc Wngers [1]. The C-terminal recently identiWed an alternatively spliced isoform des- domain of DAX1 has strongest amino acid similarity to ignated as DAX1 that speciWes a protein of 401 amino the LBD of the testis receptor, COUP-TF, and retinoid acids encoded by Exon 1 and a previously unidentiWed X receptor (RXR) [12,13]. However, the similarities with Exon 2. This isoform was shown to be expressed in a other receptors are unable to provide information broad range of tissues, but elucidation of the signiW- regarding a putative ligand, and to date, no ligand has cance and functional role of DAX1 will require further been identiWed for DAX1. DAX1 is structurally most investigation. similar to SHP, in the sense that SHP also lacks the typi- DAX1 has been classiWed as an orphan member of cal nuclear receptor DBD, but has an N-terminal the nuclear receptor superfamily [10–12]. Superfamily domain similar, but shorter than DAX1 that contains members have a characteristic domain structure consist- one 65–70 amino acid repeat, and contains a C-terminal ing of subregions A–E (Fig. 1A). The A/B region is the region homologous to nuclear receptor LBDs [14]. 62 A.K. Iyer, E.R.B. McCabe / Molecular Genetics and Metabolism 83 (2004) 60–73 Molecular mechanisms of DAX1 action thalamus, pituitary, and adrenal glands is consistent with its role as an activator, in which the loss of SF1 The complex endocrine phenotype caused by DAX1 function leads to decreased transcription of critical tar- defects is consistent with its pattern of expression get genes. On the other hand, how disruption of DAX1, throughout the hypothalamic–pituitary–adrenal– the antagonist of SF1 function, can lead to adrenal, gonadal (HPAG) axis. DAX1 expression has been hypothalamic, and pituitary developmental defects shown in the developing adrenal cortex, gonad, anterior remains a functional conundrum. pituitary, and hypothalamus, and also in adult adrenal DAX1 expression colocalizes with that of SF1 cortex, Sertoli and Leydig cells in the testis, theca, granu- [16,17]; however, the colocalization, as shown by double losa, and interstitial cells in the ovary, anterior pituitary immunoXuorescence studies, is not absolute [17]. DAX1 gonadotropes, and the ventromedial nucleus of the and SF1 show distinct expression patterns during hypothalamus [15–18].
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