A cell-specific nuclear receptor is essential for adrenal and gonadal development and sexual differentiation

Luo, Xunrong; Ikeda, Yayoi; Parker, Keith L.

doi:10.1016/0092-8674(94)90211-9

Cited by 1,501 publications

(958 citation statements)

References 22 publications

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“…This initial patient bearing the heterozygous p.Gly35Glu mutation presented with adrenal failure and gonadal dysgenesis with persistent Mullerian derivatives (Woo et al, 2015), a phenotype that closely resembled the phenotype observed in murine Nr5a1 knockout models (Luo et al, 1994). Gonadal dysgenesis and adrenal insufficiency were also present in the second reported NR5A1‐related 46,XY DSD, in a patient bearing the homozygous p.Arg92Gln mutation (Achermann et al, 2002).…”

Section: Discussionmentioning

confidence: 76%

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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Section: Discussionmentioning

confidence: 76%

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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“…Null mutations in these genes prevent gonad formation in mouse embryos. (46)(47)(48) WT1 and SF1 have roles in subsequent testis development, participating in activation of the AMH gene. (49,50) Comparisons with the chicken system have shown that the expression profiles for these genes are highly conserved prior to sexual differentiation.…”

Section: Conserved Genes Within the Pathwaymentioning

confidence: 99%

Sex determination: insights from the chicken

2004

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SummaryNot all vertebrates share the familiar system of XX:XY sex determination seen in mammals. In the chicken and other birds, sex is determined by a ZZ:ZW sex chromosome system. Gonadal development in the chicken has provided insights into the molecular genetics of vertebrate sex determination and how it has evolved. Such comparative studies show that vertebrate sex-determining pathways comprise both conserved and divergent elements. The chicken embryo resembles lower vertebrates in that estrogens play a central role in gonadal sex differentiation. However, several genes shown to be critical for mammalian sex determination are also expressed in the chicken, but their expression patterns differ, indicating functional plasticity. While the genetic trigger for sex determination in birds remains unknown, some promising candidate genes have recently emerged. The Z-linked gene, DMRT1, supports the Z-dosage model of avian sex determination. Two novel W-linked genes, ASW and FET1, represent candidate female determinants.

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“…It is well established that SF-1 is an essential regulator in endocrine tissue and organ development. Indeed, targeted disruption of sf-1 in mice results in gonadal and adrenal agenesis, as well as the complete loss of pituitary gonadotropes (Ingraham et al, 1994;Luo et al, 1994;Sadovsky et al, 1995;Shinoda et al, 1995). SF-1 also regulates multiple targets that mediate normal adult endocrine physiology (reviewed in Parker, 1998;Hammer and Ingraham, 1999) and controls male sexual differentiation by regulating three important male hormones, including the Müllerian inhibiting substance, steroidogenic enzymes for testosterone synthesis and Insl-3, which is required for testicular descent (for review, see Roberts et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Requirement of the orphan nuclear receptor SF-1 in terminal differentiation of ventromedial hypothalamic neurons

Tran

Lee

Marı́n

et al. 2003

Molecular and Cellular Neuroscience

101

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The ventromedial hypothalamic nucleus (VMN) is known to mediate autonomic responses in feeding and reproductive behaviors. To date, the most definitive molecular marker for the VMN is the orphan nuclear receptor steroidogenic factor-1 (SF-1). However, it is unclear whether SF-1 functions in the VMN as it does in peripheral endocrine organ development where loss of SF-1 results in organ agenesis due to apoptosis. Here, we provide evidence that SF-1 has a distinct role in later stages of VMN development by demonstrating the persistence of VMN precursors, the misexpression of an early marker (NKX2-1) concomitant with the absence of a late marker (BDNF neurotrophin), and the complete loss of projections to the bed nucleus of stria terminalis and the amygdala in sf-1 null mice. Our findings demonstrate that SF-1 is required for terminal differentiation of the VMN and suggest that transcriptional targets of SF-1 mediate normal circuitry between the hypothalamus and limbic structures in the telencephalon.

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A cell-specific nuclear receptor is essential for adrenal and gonadal development and sexual differentiation

Cited by 1,501 publications

References 22 publications

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

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

Sex determination: insights from the chicken

Requirement of the orphan nuclear receptor SF-1 in terminal differentiation of ventromedial hypothalamic neurons

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