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SF-1 and DAX-1

A Dynamic Duo in Endocrine Development

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Gene Engineering in Endocrinology

Part of the book series: Contemporary Endocrinology ((COE,volume 22))

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Abstract

The cloning of the first steroid/hormone nuclear receptor a decade ago has led to the identification of a multigene family with well over 60 members (1). Nuclear receptors are known to affect a wide array of important physiological effects in growth, development, and homeostasis and are key regulators of complex endocrine pathways. The field of reproductive endocrinology has been given a molecular boost by the discovery of two important members of the nuclear receptor gene family: steroidogenic factor-1 (SF-1) and DAX-1(dosage-sensitive sex-reversal adrenal hypoplasia congenita critical region of the X chromosome 1). The striking phenotypes displayed in the loss-of-function (LOF) SF-1 and DAX-1 mutants, either in mice or in men, respectively, have brought both of these gene products to the forefront of developmental endocrinology. We now appreciate that both SF-1 and DAX-1 are critical for the development of the hypothalamic-pituitary-gonadal axis and the adrenal gland. Here we explore the individual and coordinate roles of SF-1 and Dax-1 in reproductive endocrine organ development delineated from expression and genetic analyses. Additionally, we present the current understanding of the physical and functional interactions between these two nuclear receptors. Finally, we highlight the major unresolved questions that have emerged for those wishing to understand the molecular and genetic nature of the SF-1 and Dax-1 partnership.

SF-1 and Dax-1: divergent members of a supergene family. (A) Schematic representation of mouse SF-1 and mDax-1, with corresponding amino acids is shown. The classic DBD consisting of two Cys2-Cys2 zinc finger motifs, a hinge region, and a putative LBD of SF-1 is shown. Two regions important for transactivation function are also shown, AF-1 and AF-2. Arrows indicate the three and half cysteine-alanine-glycine-rich repeats and solid black bars indicate the approximate location of the silencing domains. Putative LBD regions for both SF-1 and Dax-1 are shown based on sequence identity with other steroid/hormone nuclear receptors. Based on high-resolution structural analyses of other nuclear receptors, the LBD of SF-1 might begin at residue 221. (B) Classic nuclear receptors bind discrete DNA response elements in a homo- or heterodimeric fashion and can affect transcription in a ligand- (triangle) dependent manner. SF-1 binds DNA as a monomer to stimulate transcription in the absence of ligand; however, an unknown ligand may modulate SF-1 activity (?). Dax-1 is unable to bind to classic nuclear hormone receptor response elements, but has been shown to bind DNA hairpin loops (31). Similar to SF-1, a ligand for Dax-1 has not been identified.

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Authors
  1. Mark W. Nachtigal PhD
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  2. Debra Enyeart-VanHouten MS
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  3. Holly A. Ingraham PhD
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Editors and Affiliations

  1. Division of Endocrinology, Department of Internal Medicine, University of Virginia Health Sciences Center, Charlottesville, VA, USA

    Margaret A. Shupnik PhD

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Nachtigal, M.W., Enyeart-VanHouten, D., Ingraham, H.A. (2000). SF-1 and DAX-1. In: Shupnik, M.A. (eds) Gene Engineering in Endocrinology. Contemporary Endocrinology, vol 22. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-59259-221-0_9

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  • DOI: https://doi.org/10.1007/978-1-59259-221-0_9

  • Publisher Name: Humana Press, Totowa, NJ

  • Print ISBN: 978-1-61737-147-9

  • Online ISBN: 978-1-59259-221-0

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