X-linked Gene for Testicular Feminization in the Mouse

Lyon, Mary F.; Hawkes, S

doi:10.1038/2271217a0

Cited by 532 publications

(224 citation statements)

References 13 publications

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“…The anogenital distance was shortened in Fkbp52-deficient males (3-10 weeks of age) (Fig. 1D), a feminization phenotype similar to that seen in ARKO and testicular feminization (tfm) mice, albeit to a lesser degree (8,10).…”

Section: Resultsmentioning

confidence: 88%

“…For example, the AR-deficient (androgen receptor knock-out; ARKO) mouse (8) and the tfm (testicular feminization mutant) mouse (9) both develop severe defects of testicular development and an overall lack of male sexual differentiation, including hypospadias and penile agenesis. The tfm male mouse demonstrates many female secondary structures, including vagina and teats (10).…”

Section: Androgen Receptor (Ar)mentioning

confidence: 99%

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Essential Role for Co-chaperone Fkbp52 but Not Fkbp51 in Androgen Receptor-mediated Signaling and Physiology

Yong

Yang

Periyasamy

et al. 2007

Journal of Biological Chemistry

139

173

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Androgen receptor (AR)3 is a hormone-induced transcription factor that controls male sexual development and other important physiologies. Similar to other members of the nuclear receptor family (1, 2), AR has three major functional domains: an N-terminal transactivation domain, a DNA-binding domain, and a C-terminal ligand-binding domain (3-5). Mutations found in each of these domains lead to a series of AR functional defects associated with androgen insensitivity syndrome (AIS) or partial AIS in humans (6, 7). The majority of AIS and partial AIS patients have developmental defects in the male reproductive system. Loss-of-function AR mutations in mice recapitulate many of the reproductive defects found in AIS patients. For example, the AR-deficient (androgen receptor knock-out; ARKO) mouse (8) and the tfm (testicular feminization mutant) mouse (9) both develop severe defects of testicular development and an overall lack of male sexual differentiation, including hypospadias and penile agenesis. The tfm male mouse demonstrates many female secondary structures, including vagina and teats (10).Molecular regulation of AR function can be achieved at several levels, such as spatial-temporal expression of the receptor, modulation of ligand binding, cytoplasm to nucleus translocation, and DNA binding and transcriptional activities (11,12). Prior to hormone binding, steroid receptors form large protein complexes containing the molecular chaperone heat shock protein 90 (Hsp90) as well as various co-chaperone tetratricopeptide repeat (TPR) proteins (13-15). These co-chaperones include Fkbp52 and Fkbp51 (FK506-binding protein 52 and 51, respectively), Cyp40 (cyclophilin 40), and PP5 (protein phosphatase 5). Fkbp52 and Fkbp51 are ubiquitously expressed proteins with peptidyl prolyl cis/trans-isomerase activity that is inhibited by the binding of . Each TPR protein enters into steroid receptor complexes through a direct and competitive binding at the C terminus of Hsp90 via its essential TPR domain (19 -21). Although Fkbp52 and Fkbp51 share a similar domain structure, as well as 60% sequence identity and 75% similarity, they do differ in that Fkbp51 is missing a C-terminal calmodulin-binding domain.To date, most studies on TPR control of the steroid receptor (SR) action have been done using conventional molecular and cellular approaches and using the glucocorticoid (GR) and progesterone (PR) receptors as models. It has been shown that Fkbp52 is localized to both cytoplasm and nucleus but that the cytoplasmic fraction co-localizes with microtubules in a complex containing dynein (22, 23). For these reasons, it was pro-

show abstract

Section: Resultsmentioning

confidence: 88%

Section: Androgen Receptor (Ar)mentioning

confidence: 99%

Essential Role for Co-chaperone Fkbp52 but Not Fkbp51 in Androgen Receptor-mediated Signaling and Physiology

Yong

Yang

Periyasamy

et al. 2007

Journal of Biological Chemistry

139

173

View full text Add to dashboard Cite

show abstract

“…androgen signaling. Mice with mutations in the androgen receptor (AR) or 5α-reductase, which converts testosterone to dihydrotestosterone, develop feminized external genitalia (19,20). In humans, mutations in these genes underlie androgen insensitivity syndrome, in which genetic males fail to respond to androgen signaling and consequently develop feminized genitalia and secondary sex characters (21).…”

mentioning

confidence: 99%

Timing of androgen receptor disruption and estrogen exposure underlies a spectrum of congenital penile anomalies

Zheng

Armfield

Cohn

2015

Proc. Natl. Acad. Sci. U.S.A.

105

129

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Congenital penile anomalies (CPAs) are among the most common human birth defects. Reports of CPAs, which include hypospadias, chordee, micropenis, and ambiguous genitalia, have risen sharply in recent decades, but the causes of these malformations are rarely identified. Both genetic anomalies and environmental factors, such as antiandrogenic and estrogenic endocrine disrupting chemicals (EDCs), are suspected to cause CPAs; however, little is known about the temporal window(s) of sensitivity to EDCs, or the tissue-specific roles and downstream targets of the androgen receptor (AR) in external genitalia. Here, we show that the full spectrum of CPAs can be produced by disrupting AR at different developmental stages and in specific cell types in the mouse genital tubercle. Inactivation of AR during a narrow window of prenatal development results in hypospadias and chordee, whereas earlier disruptions cause ambiguous genitalia and later disruptions cause micropenis. The neonatal phase of penile development is controlled by the balance of AR to estrogen receptor α (ERα) activity; either inhibition of androgen or augmentation of estrogen signaling can induce micropenis. AR and ERα have opposite effects on cell division, apoptosis, and regulation of Hedgehog, fibroblast growth factor, bone morphogenetic protein, and Wnt signaling in the genital tubercle. We identify Indian hedgehog (Ihh) as a novel downstream target of AR in external genitalia and show that conditional deletion of Ihh inhibits penile masculinization. These studies reveal previously unidentified cellular and molecular mechanisms by which antiandrogenic and estrogenic signals induce penile malformations and demonstrate that the timing of endocrine disruption can determine the type of CPA.sexual differentiation | external genitalia | congenital malformation | androgen | hypospadias

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“…In adult FSHRKO mice Sertoli cell number is reduced but the animals are fertile (Dierich et al, 1998;Abel et al, 2000). In contrast, Tfm mice or mice lacking androgen receptors (AR) specifically in the Sertoli cells (SCARKO) are infertile due to a failure of spermatogenic progression beyond early meiosis (Lyon and Hawkes, 1970;De Gendt et al, 2004;Holdcraft and Braun, 2004;Chang et al, 2004). This highlights the importance of androgens in the regulation of Sertoli cell activity and a number of studies have used microarray technology to try to identify the major targets of androgen action in the Sertoli cell.…”

Section: Post-natal Developmentmentioning

confidence: 99%

Role of androgen and gonadotrophins in the development and function of the Sertoli cells and Leydig cells: Data from mutant and genetically modified mice

O’Shaughnessy

Morris

Huhtaniemi

et al. 2009

Molecular and Cellular Endocrinology

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X-linked Gene for Testicular Feminization in the Mouse

Cited by 532 publications

References 13 publications

Essential Role for Co-chaperone Fkbp52 but Not Fkbp51 in Androgen Receptor-mediated Signaling and Physiology

Essential Role for Co-chaperone Fkbp52 but Not Fkbp51 in Androgen Receptor-mediated Signaling and Physiology

Timing of androgen receptor disruption and estrogen exposure underlies a spectrum of congenital penile anomalies

Role of androgen and gonadotrophins in the development and function of the Sertoli cells and Leydig cells: Data from mutant and genetically modified mice

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