Expression of steroidogenic factor 1 and Wilms' tumour 1 during early human gonadal development and sex determination

Hanley, Neil A.; Ball, Steve; Clement-Jones, Mark; Hagan, Donna Marie; Strachan, Tom; Lindsay, Susan; Robson, Samuel; Ostrer, Harry; Parker, Keith L.; Wilson, D.I.

doi:10.1016/s0925-4773(99)00123-9

Cited by 163 publications

(126 citation statements)

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“…In humans, WT1 expression first appears at 32 days postovulation (d.p.o. ) in the gonadal ridges of both male and female embryos and then increases at 41 d.p.o., whereas SRY is most strongly expressed at 44 d.p.o., and both genes are expressed later in fetal development (Hanley et al, 1999(Hanley et al, , 2000. Furthermore, mutations in both genes are associated with gonadal dysgenesis in mice and humans as described above.…”

mentioning

confidence: 87%

Transcriptional activity of testis-determining factor SRY is modulated by the Wilms’ tumor 1 gene product, WT1

2003

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The Wilms' tumor 1 (WT1) and sex-determining region of the Y chromosome (SRY) genes are essential for development of the mammalian gonads and mutations in these genes are associated with gonadal dysgenesis in humans. The SRY gene encodes a transcription factor with one high-mobility group (HMG) box as a DNAbinding domain. WT1 encodes a transcription factor that contains four contiguous C 2 H 2 -type zinc-finger motifs as a DNA/RNA binding or protein-protein interaction domain. Here we report that WT1 binds to and acts synergistically with SRY to activate transcription from a promoter containing SRY-binding sites. This interaction is mediated by the WT1 zinc-finger domain and the SRY HMG box. WT1 mutants associated with Denys-Drash syndrome (DDS), which is characterized by Wilms' tumor, pseudohermaphroditism, and nephropathy, fail to interact with SRY. Wildtype WT1 is recruited to SRYbinding sites in an SRY-dependent manner, whereas DDS mutants are not recruited as efficiently. These results suggest that WT1 forms a complex with SRY to regulate transcription and that this WT1-SRY interaction is important in testis development.

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confidence: 87%

Transcriptional activity of testis-determining factor SRY is modulated by the Wilms’ tumor 1 gene product, WT1

2003

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“…(see Table). The embryos were fixed overnight in 4 % paraformaldehyde in phosphate-buffered saline and embedded in paraffin wax using a standard protocol (Hanley et al 1999).…”

Section: mentioning

confidence: 99%

“…Dated mating was identified by the presence of a vaginal mucous plug which was considered to be embryonic day zero. Mouse embryos of E9n5-13n5 were obtained, fixed in 4 % paraformaldehyde in phosphate buffered saline and embedded in paraffin wax (Hanley et al 1999).…”

Section: mentioning

confidence: 99%

“…A 608 bp fragment of the human AFP gene spanning exons 10-14 was used as a template to make sense and antisense RNA probes (Accession number T56880, IMAGE clone 68265) and a 384 bp fragment of the mouse AFP gene spanning exons 12-15 (Accession number W09511, IMAGE clone 303929). RNA probes were labelled with $&S using RNA in vitro transcription and in situ hybridisations were performed as previously described (Hanley et al 1999).…”

Section: mentioning

confidence: 99%

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Differences between human and mouse alpha‐fetoprotein expression during early development

et al. 2001

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Alpha-fetoprotein (AFP) is the major serum protein during development. AFP is one of the earliest proteins to be synthesised by the embryonic liver. The synthesis of AFP decreases dramatically after birth and only trace amounts are expressed in the adult liver. The tissue distribution of AFP in early human embryogenesis has not been defined. We have studied the expression pattern of AFP mRNA in human and mouse embryos by in situ hybridisation. In humans, AFP is expressed in the hepatic diverticulum at 26 d postovulation as it differentiates from the foregut endoderm (i.e. in the most primitive hepatocytes). It is also expressed in the endoderm of the gastrointestinal tract and in the yolk sac at this age. AFP is subsequently expressed in the mesonephros and transiently in the developing pancreas. In the mouse, no expression of AFP was observed in the mesonephros but other sites of expression were similar. Thus AFP has a distinct temporospatial expression pattern during the embryonic period and this differs between human and mouse species. It is interesting that AFP is expressed by tumours such as primitive gastrointestinal, renal cell and pancreatic tumours as well as those of hepatocyte origin. This distribution reflects the sites of AFP expression during development.

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“…In developing embryos, Nr5a1 is expressed in the urogenital ridge, representing the first marker of gonadal and adrenal differentiation (Ikeda et al, 1994; Morohashi et al, 1995, 1999; Ramayya et al, 1997; Hanley et al, 1999, 2001). Throughout human development, NR5A1 is expressed in the steroid‐secreting adrenal cortex, in Leydig and Sertoli cells, as well as in granulosa and theca cells.…”

Section: Introductionmentioning

confidence: 99%

Wide spectrum of NR5A1‐related phenotypes in 46,XY and 46,XX individuals

Domenice¹,

Machado²,

Ferreira

et al. 2016

Birth Defects Research Pt C

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Steroidogenic factor 1 (NR5A1, SF‐1, Ad4BP) is a transcriptional regulator of genes involved in adrenal and gonadal development and function. Mutations in NR5A1 have been among the most frequently identified genetic causes of gonadal development disorders and are associated with a wide phenotypic spectrum. In 46,XY individuals, NR5A1‐related phenotypes may range from disorders of sex development (DSD) to oligo/azoospermia, and in 46,XX individuals, from 46,XX ovotesticular and testicular DSD to primary ovarian insufficiency (POI). The most common 46,XY phenotype is atypical or female external genitalia with clitoromegaly, palpable gonads, and absence of Müllerian derivatives. Notably, an undervirilized external genitalia is frequently seen at birth, while spontaneous virilization may occur later, at puberty. In 46,XX individuals, NR5A1 mutations are a rare genetic cause of POI, manifesting as primary or secondary amenorrhea, infertility, hypoestrogenism, and elevated gonadotropin levels. Mothers and sisters of 46,XY DSD patients carrying heterozygous NR5A1 mutations may develop POI, and therefore require appropriate counseling. Moreover, the recurrent heterozygous p.Arg92Trp NR5A1 mutation is associated with variable degrees of testis development in 46,XX patients. A clear genotype‐phenotype correlation is not seen in patients bearing NR5A1 mutations, suggesting that genetic modifiers, such as pathogenic variants in other testis/ovarian‐determining genes, may contribute to the phenotypic expression. Here, we review the published literature on NR5A1‐related disease, and discuss our findings at a single tertiary center in Brazil, including ten novel NR5A1 mutations identified in 46,XY DSD patients. The ever‐expanding phenotypic range associated with NR5A1 variants in XY and XX individuals confirms its pivotal role in reproductive biology, and should alert clinicians to the possibility of NR5A1 defects in a variety of phenotypes presenting with gonadal dysfunction. Birth Defects Research (Part C) 108:309–320, 2016. © 2016 The Authors Birth Defects Research Part C: Embryo Today: Reviews Published by Wiley Periodicals, Inc.

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Expression of steroidogenic factor 1 and Wilms' tumour 1 during early human gonadal development and sex determination

Cited by 163 publications

References 8 publications

Transcriptional activity of testis-determining factor SRY is modulated by the Wilms’ tumor 1 gene product, WT1

Transcriptional activity of testis-determining factor SRY is modulated by the Wilms’ tumor 1 gene product, WT1

Differences between human and mouse alpha‐fetoprotein expression during early development

Wide spectrum of NR5A1‐related phenotypes in 46,XY and 46,XX individuals

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