Of sex and determination: marking 25 years of Randy, the sex-reversed mouse

Koopman, Peter; Sinclair, Andrew H.; Lovell-Badge, Robin

doi:10.1242/dev.137372

Cited by 19 publications

(8 citation statements)

References 46 publications

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“…In the early 1990s, SRY (‘sex-determining region Y protein’) was identified as the main Y-chromosomal driver for testis development, supported by the generation of ‘Randy’, an XX mouse that developed testes and a male phenotype owing to the presence of a Sry transgene [1]. SRY is also crucially important in human testis determination, although only approximately 5% of individuals with testicular dysgenesis have disruption of this transcription factor.…”

Section: Human Sex Developmentmentioning

confidence: 99%

Human sex development: targeted technologies to improve diagnosis

Buonocore

Achermann

2016

Genome Biol

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Section: Human Sex Developmentmentioning

confidence: 99%

Human sex development: targeted technologies to improve diagnosis

Buonocore

Achermann

2016

Genome Biol

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“…Studies in transgenic mice and humans with SRY deletions and translocations have suggested that SRY is the primary Y-chromosomal testis-determining gene in humans, but direct evidence is limited (Bashamboo et al, 2017; Hanley et al, 2000; Koopman et al, 2016). SRY is thought to be transiently up-regulated in the 46,XY bipotential gonad at around 42 dpc, leading to downstream expression of testis development pathways (Hanley et al, 2000).…”

Section: Resultsmentioning

confidence: 99%

“…The role of SRY as the primary testis-determining gene has been known for 25 years, following transgenic mouse studies as well as the discovery of duplication of SRY in individuals with 46,XX testicular disorders of sex development (DSD) or disruption of SRY in 46,XY testicular dysgenesis (Bashamboo et al, 2017; Koopman et al, 2016; Svingen & Koopman, 2013). SRY is believed to undergo a transient wave of expression in the developing testis that regulates transcription of downstream factors such as SOX9 and initiates testis development pathways (Hiramatsu et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

“…In the developing 46,XY embryo, transient expression of the testis-determining gene, SRY , on the Y chromosome is believed to lead to upregulation of genes such as SOX9 and the process of testis determination (Bashamboo et al, 2017; Hanley et al, 2000; Hiramatsu et al, 2009; Koopman et al, 2016; Sekido & Lovell-Badge, 2008). At around 7–8 weeks post conception (wpc), Sertoli cells secrete the peptide hormone Anti-Müllerian Hormone (AMH, also known as Müllerian Inhibiting Substance, MIS) to regress Müllerian structures (uterus and upper vagina).…”

Section: Introductionmentioning

confidence: 99%

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A genomic atlas of human adrenal and gonad development

Valle¹,

Buonocore²,

Duncan³

et al. 2017

Wellcome Open Res

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In humans, the adrenal glands and gonads undergo distinct Background biological events between 6-10 weeks post conception (wpc), such as testis determination, the onset of steroidogenesis and primordial germ cell development. However, relatively little is currently known about the genetic mechanisms underlying these processes. We therefore aimed to generate a detailed genomic atlas of adrenal and gonad development across these critical stages of human embryonic and fetal development.: RNA was extracted from 53 tissue samples between 6-10 wpc Methods (adrenal, testis, ovary and control). Affymetrix array analysis was performed and differential gene expression was analysed using Bioconductor. A mathematical model was constructed to investigate time-series changes across the dataset. Pathway analysis was performed using ClueGo and cellular localisation of novel factors confirmed using immunohistochemistry.: Using this approach, we have identified novel components of adrenal Results development (e.g. , ) and confirmed the role of as the main ASB4 NPR3 SRY human testis-determining gene. By mathematical modelling time-series data we have found new genes up-regulated with in the testis (e.g. ), SOX9 CITED1 which may represent components of the testis development pathway. We have shown that testicular steroidogenesis has a distinct onset at around 8 wpc and identified potential novel components in adrenal and testicular steroidogenesis (e.g. , ,

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“…Human sex development is dictated by the inheritance of either an X or Y chromosome from the father to offspring. The male sex determination step starts with the expression of a Y-chromosome-encoded transcription factor SRY (sex-determining region Y) in the bipotential gonad, initiating a cascade of molecular and cellular events leading to testicular organogenesis [ 1 ]. In the absence of the Y chromosome, female-specific pathways are initiated for proper ovarian development [ 2 ].…”

Section: Introductionmentioning

confidence: 99%

Identification of novel candidate genes for 46,XY disorders of sex development (DSD) using a C57BL/6J-Y POS mouse model

et al. 2018

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BackgroundDisorders of sex development (DSD) have an estimated frequency of 0.5% of live births encompassing a variety of urogenital anomalies ranging from mild hypospadias to a discrepancy between sex chromosomes and external genitalia. In order to identify the underlying genetic etiology, we had performed exome sequencing in a subset of DSD cases with 46,XY karyotype and were able to identify the causative genetic variant in 35% of cases. While the genetic etiology was not ascertained in more than half of the cases, a large number of variants of unknown clinical significance (VUS) were identified in those exomes.MethodsTo investigate the relevance of these VUS in regards to the patient’s phenotype, we utilized a mouse model in which the presence of a Y chromosome from the poschiavinus strain (YPOS) on a C57BL/6J (B6) background results in XY undervirilization and sex reversal, a phenotype characteristic to a large subset of human 46,XY DSD cases. We assessed gene expression differences between B6-YB6 and undervirilized B6-YPOS gonads at E11.5 and identified 515 differentially expressed genes (308 underexpressed and 207 overexpressed in B6-YPOS males).ResultsWe identified 15 novel candidate genes potentially involved in 46,XY DSD pathogenesis by filtering the list of human VUS-carrying genes provided by exome sequencing with the list of differentially expressed genes from B6-YPOS mouse model. Additionally, we identified that 7 of the 15 candidate genes were significantly underexpressed in the XY gonads of mice with suppressed Sox9 expression in Sertoli cells suggesting that some of the candidate genes may be downstream of a well-known sex determining gene, Sox9.ConclusionThe use of a DSD-specific animal model improves variant interpretation by correlating human sequence variants with transcriptome variation.Electronic supplementary materialThe online version of this article (10.1186/s13293-018-0167-9) contains supplementary material, which is available to authorized users.

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Of sex and determination: marking 25 years of Randy, the sex-reversed mouse

Cited by 19 publications

References 46 publications

Human sex development: targeted technologies to improve diagnosis

Human sex development: targeted technologies to improve diagnosis

A genomic atlas of human adrenal and gonad development

Identification of novel candidate genes for 46,XY disorders of sex development (DSD) using a C57BL/6J-Y POS mouse model

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