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DAX-1/Nuclear receptor subfamily 0, group B, member 1 (Gene NROB1) Homo sapiensThe X-chromosome-linked NROB1 gene (map locus Entrez: Xp21.3-p21.2; Ensembl: Xp21.2; HGNC: Xp21.3) product, nuclear receptor DAX-1 (dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1), is translated as two splice variants. NROB1A and NROB1 are 400 amino acids long, Ho J, et al. (2004) and 470 amino acids long (51.7 kDa), respectively. NROB1A is the more abundant form in most tissues except testis. It results from the removal of the C-terminal 70 amino acids and changes in the 10 amino acids of the new C-terminal (390 to 400). NROB1A lacks the AF-2 binding motif found in the long form. Both variants contain three LXXLL motifs, ligand-binding domains (LBD) and 4 N-terminal repeats that are believed to bind DNA stem loop structures in lieu of zinc finger DNA-binding domains characteristic of other nuclear receptors. DAX1 variants exist as homodimers and heterodimers with variant partnering (NROB1:NROB1A) and with SHP (NROB1:NROB2); consequently these gene products are complex and will require extensive new studies to fully define their roles, McCabe ER. (2007). DAX-1 is expressed in tissue of the HPAG-axis including; the hypothalamus, pituitary, adrenal cortex and gonads. DAX-1 expression in a human adrenocortical carcinoma line, NC1-H295, with fetal adrenal cortex-like features suggested that it may have a role in steroidogenesis , Guo W, et al. (1995). It is now known that DAX-1 along with its network proteins (Nanog, SF-1, Wt1) is also expressed in totipotent embryonic stem cells, and preimplantation embryos, Chipsham R, et al. (2004); Niakan KK, et al. (2005). DAX1, AHCH, was initially discovered as a component of the cascade that regulates development of the hypothalamic-pituitary-adrenal-gonadal axis (HPAG axis). DAX-1 acts as a dominant transcription repressor in hormone-producing tissues of the HPAG axis. It coregulates the embryonic development of these tissues and hormone production in formed tissues. NROB1 along with WT1, SOX9, ATRX and SRY, has been identified as a sex-determining gene, in human sex reversal, XY females and XX males, McElreavey K and Fellous M. (1997); Kojima, Y, et al. (2008). DAX-1 has emerged as a negative coregulator of genes involved in the HPAG axis and maintenance of pluripotency. The growing list includes estrogen receptor (ER, NR3A1-2); liver receptor homologue-1 (LRH-1); steroidogenesis factor, (NR5A1, SF-1); NR5A2, androgen receptor (AR, NR3C4); progesterone receptor (PR, NR3C3), Iyer AK, et al. (2004) and peroxisome proliferators-activated receptor (PPARgamma), Kim GS, et al. (2008). DAX-1 represses transcription of genes that are regulated by steroidogenic factor-1 (SF-1, NR5A1), Suzuki T, (2003), an orphan nuclear receptor required for development of the urogenital ridge, adrenal glands and gonads, Ito M, et al. (1997). DAX-1 acts as an adaptor molecule that recruits corepressors such as N-CoR to SF-1, Crawford PA, et al. (1998). Contrary to its repressor function, DAX1 and SF-1 have been reported to function cooperatively to mediate somatic cell differentiation during testis development, Park SY, (2005). Mutations in NROB1 cause X-linked cytomegalic form of adrenal hypoplasia congenita (AHC). AHC results in adrenal gland structural disorder, congenital adrenal hypoplasia leading to hormone deficiencies and hypogonadotropic hypogonadism (HHG). AHC is lethal if untreated. Duplication of DAX-1 causes dosage sensitive sex reversal (DSS), XY phenotypic females. An understanding of the role of DAX1 in pluripotent cells is beginning to emerge. DAX1 as a nuclear receptor involved with ES cell pluripotency and differentiation has been recently reviewed, Mullen EM, (2007). DAX1 is a component of the protein interaction network, cellular module, dedicated to pluripotency, Wang J, et al. (2006); Pan G and Thomson JA (2007); Kim J, (2008). Sigma offers antibodies, shRNAs and other products useful for the study of the Dax1 gene. References: Clipsham R, et al. (2004) Nr0b1 and its network partners are expressed early in murine embryos prior to steroidogenic axis organogenesis. Gene Expr Patterns. 4: 3-14. |
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