The effect of oestrogen and testosterone on the urethral seam of the developing male mouse genital tubercle

Yücel, Selçuk; Cavalcanti, André G.; DeSouza, Antonio Carlos; Wang, Z; Baskin, Laurence S.

doi:10.1111/j.1464-410x.2003.04511.x

Cited by 48 publications

(33 citation statements)

References 26 publications

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“…It is possible that variants in the ATF3 sequence and/or environmental mechanisms, such as endocrine disrupters (9,10,12) and lower nutrient availability (35) (a link to low birth weight? (4)) lead to inappropriate regulation of ATF3, which might halter the seam fusion process of the developing urethra, by suppressing cell growth and/or promoting cell death, by disturbing hormonal signaling, or by impairing epithelial-mesenchymal differentiation, and result in a shorter urethra with a proximal opening.…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, the importance of estrogens in male reproductive tract development has been increasingly acknowledged. Functional Estrogen Receptors (ESR)s were detected in differentiating male external genitalia localized at the same structures as the androgen receptors, indicating interactions between effects exerted by the two steroid hormones (7,8); and an excess of estrogens in the developing murine urethra results in an inhibition of the cell proliferation in a dose-dependent manner (9). Moreover, hypospadias has been induced in a mice model by maternal exposure to synthetic estrogens during pregnancy (10).…”

Section: Introductionmentioning

confidence: 99%

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Activating transcription factor 3: a hormone responsive gene in the etiology of hypospadias

Beleza-Meireles

Töhönen

Söderhäll

et al. 2008

European Journal of Endocrinology

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Introduction: Hypospadias is a common inborn error of the genital development, whose complex etiology remains elusive. Defects of the androgen metabolism and activity have been found in a subset of boys with hypospadias. Moreover, the balance between androgens and estrogens seems to be important to the proper male genital development. Activating transcription factor 3 (ATF3), an estrogen responsive gene, has been reported to be expressed during sexual development and up-regulated in hypospadic genital skin. We investigated ATF3 as a candidate gene for hypospadias. Material and methods: Genotyping of eight-tagged single nucleotide polymorphisms (SNP)s was performed in 330 boys with hypospadias and in 380 healthy controls. Screening for mutations in ATF3 was conducted in a subset of boys with hypospadias. ATF3 expression was evaluated in the foreskin of boys with hypospadias and in healthy controls and in the human fetal genitalia by immunohistochemistry. Results: Three common SNPs, spanning a region of about 16 kb in intron 1 of ATF3, are associated with hypospadias. These SNPs are not linked and their effects are independent. The combination of the three risk SNPs yields the highest significance. Mutation screening identified the gene variant c536AOG in one patient and c817COT in the 3 0 -UTR in two other patients. ATF3 expression was evidenced in the developing male urethra. Conclusions: ATF3 gene variants influence the risk of hypospadias. Its hormonal responsiveness may underlie this risk effect. But also other ATF3-dependent biological aspects, such as cell survival and death, response to stress stimuli, or the control of epithelial-mesenchymal interactions, may be of importance.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Activating transcription factor 3: a hormone responsive gene in the etiology of hypospadias

Beleza-Meireles

Töhönen

Söderhäll

et al. 2008

European Journal of Endocrinology

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“…[32][33][34] Postnatally, the urethral meatus forms via fusion of elements that constitute the urethral meatus. 35,36 this fusion process is inferred from raphes, midline clefts and processes that define the adult mouse urethral meatus (Figures 4a and 5a-c). these two mechanistic scenarios are not mutually exclusive.…”

Section: 31mentioning

confidence: 99%

Current understanding of hypospadias: relevance of animal models

et al. 2015

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| Hypospadias is a congenital abnormality of the penile urethra with an incidence of approximately 1:200-1:300 male births, which has doubled over the past three decades. The aetiology of the overwhelming majority of hypospadias remains unknown but appears to be a combination of genetic susceptibility and prenatal exposure to endocrine disruptors. Reliable animal models of hypospadias are required for better understanding of the mechanisms of normal penile urethral formation and hence hypospadias. Mice and/ or rats are generally used for experimental modelling of hypospadias, however these do not fully reflect the human condition. To use these models successfully, researchers must understand the similarities and differences between mouse, rat and human penile anatomy as well as the normal morphogenetic mechanisms of penile development in these species. Despite some important differences, numerous features of animal and human hypospadias are shared: the prevalence of distal penile malformations; disruption of the urethral meatus; disruption of urethra-associated erectile bodies; and a common mechanism of impaired epithelial fusion events. Rat and mouse models of hypospadias are crucial to our understanding of hypospadias to ultimately reduce its incidence through better preventive strategies.

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“…Isolated embryos and tissue samples were fixed in 10% neutral-buffered formalin, paraffin-embedded, and sectioned (6 m) and stained with hematoxylin and eosin. Three-dimensional reconstruction was carried out as previously described (37). Immunohistological analysis was carried out as previously described (38).…”

Section: Generation Of Fkbp52-deficient Mice and Fkbp51-deficientmentioning

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

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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-

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The effect of oestrogen and testosterone on the urethral seam of the developing male mouse genital tubercle

Cited by 48 publications

References 26 publications

Activating transcription factor 3: a hormone responsive gene in the etiology of hypospadias

Activating transcription factor 3: a hormone responsive gene in the etiology of hypospadias

Current understanding of hypospadias: relevance of animal models

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

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