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Deletion of Wt1 during early gonadogenesis leads to differences of sex development in male and female adult mice.

ABSTRACT: Assessing the role of the WT1 transcription factor (WT1) during early gonad differentiation and its impact on adult sex development has been difficult due to the complete gonadal agenesis and embryonic lethality exhibited by Wt1KO mouse models. Here, we generated Wt1LoxP/GFP;Wt1Cre mice, the first Wt1KO mouse model that reaches adulthood with a dramatically reduced Wt1 expression during early gonadogenesis. Wt1LoxP/GFP;Wt1Cre mice lacked mature gonads and displayed genital tracts containing both male and female genital structures and ambiguous genitalia. We found that WT1 is necessary for the activation of both male and female sex-determining pathways, as embryonic mutant gonads failed to upregulate the expression of the genes specific for each genetic programme. The gonads of Wt1LoxP/GFP;Wt1Cre mice showed a lack of production of Sertoli and pre-granulosa cells and a reduced number of germ cells. NR5A1 and the steroidogenic genes expression was modulated differently in XY and XX Wt1LoxP/GFP;Wt1Cre gonads, explaining the mutant phenotypes. Further studies of the XX Wt1LoxP/GFP;Wt1Cre gonads revealed that deletion of WT1 at an early stage impaired the differentiation of several cell types including somatic cells and the ovarian epithelium. Through the characterisation of this Wt1KO mouse model, we show that the deletion of Wt1 during early gonadogenesis produces dramatic defects in adult sex development.

SUBMITTER: Torres-Cano A

PROVIDER: S-EPMC9200307 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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Deletion of Wt1 during early gonadogenesis leads to differences of sex development in male and female adult mice.

Torres-Cano Alejo A Portella-Fortuny Rosa R Müller-Sánchez Claudia C Porras-Marfil Sonia S Ramiro-Pareta Marina M Chau You-Ying YY Reina Manuel M Soriano Francesc X FX Martínez-Estrada Ofelia M OM

PLoS genetics 20220615 6

Assessing the role of the WT1 transcription factor (WT1) during early gonad differentiation and its impact on adult sex development has been difficult due to the complete gonadal agenesis and embryonic lethality exhibited by Wt1KO mouse models. Here, we generated Wt1LoxP/GFP;Wt1Cre mice, the first Wt1KO mouse model that reaches adulthood with a dramatically reduced Wt1 expression during early gonadogenesis. Wt1LoxP/GFP;Wt1Cre mice lacked mature gonads and displayed genital tracts containing both ...[more]

PMID: 35704566

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Project description:BackgroundBehavioral sex differences are widespread in the animal world. These differences can be qualitative (i.e., behavior present in one sex but not the other, a true sex dimorphism) or quantitative (behavior is present at a higher rate or quality in one sex compared to the other). Singing in oscine songbirds is associated with both types of differences. In canaries, female rarely sing spontaneously but they can be induced to do so by treatments with steroids. Song in these females is, however, not fully masculinized and exhibits relatively subtle differences in quality as compared with male song. We analyzed here sex differences in syllable content and syllable use between singing male and female canaries.MethodsSongs were recorded from three groups of castrated male and three groups of photoregressed female canaries that had received Silastic™ implants filled with testosterone (T), with T plus estradiol (E2), or left empty (control). After 6 weeks of hormone treatment, 30 songs were recorded from each of the 47 subjects. Songs were segmented and each syllable was annotated. Various metrics of syllable diversity were extracted and network analysis was employed to characterize syllable sequences.ResultsMale and female songs were characterized by marked sex differences related to syllable use. Compared to females, males had a larger syllable-type repertoire and their songs contained more syllable types. Network analysis of syllable sequences showed that males follow more fixed patterns of syllable transitions than females. Both sexes, however, produced song of the same duration containing the same number of syllables produced at similar rates (numbers per second).ConclusionsUnder the influence of T, canaries of both sexes are able to produce generally similar vocalizations that nevertheless differ in specific ways. The development of song during ontogeny appears to be a very sophisticated process that is presumably based on genetic and endocrine mechanisms but also on specific learning processes. These data highlight the importance of detailed behavioral analyses to identify the many dimensions of a behavior that can differ between males and females.

Project description:ImportanceStudies have found that female surgeons have fewer opportunities to perform highly remunerated operations, a circumstance that contributes to the sex-based pay gap in surgery. Procedures performed by surgeons are, in part, determined by the referrals they receive. In the US and Canada, most practicing physicians who provide referrals are men. Whether there are sex-based differences in surgical referrals is unknown.ObjectiveTo examine whether physicians' referrals to surgeons are influenced by the sex of the referring physician and/or surgeon.Design, setting, and participantsThis cross-sectional, population-based study used administrative databases to identify outpatient referrals to surgeons in Ontario, Canada, from January 1, 1997, to December 31, 2016, with follow-up to December 31, 2018. Data analysis was performed from April 7, 2019, to May 14, 2021.ExposuresReferring physician sex.Main outcomes and measuresThis study compared the proportion of referrals (overall and those referrals that led to surgery) made by male and female physicians to male and female surgeons to assess associations between surgeon, referring physician, or patient characteristics and referral decisions. Discrete choice modeling was used to examine the extent to which sex differences in referrals were associated with physicians' preferences for same-sex surgeons.ResultsA total of 39 710 784 referrals were made by 44 893 physicians (27 792 [61.9%] male) to 5660 surgeons (4389 [77.5%] male). Female patients made up a greater proportion of referrals to female surgeons than to male surgeons (76.8% vs 55.3%, P < .001). Male surgeons accounted for 77.5% of all surgeons but received 87.1% of referrals from male physicians and 79.3% of referrals from female physicians. Female surgeons less commonly received procedural referrals than male surgeons (25.4% vs 33.0%, P < .001). After adjusting for patient and referring physician characteristics, male physicians referred a greater proportion of patients to male surgeons than did female physicians; differences were greatest among referrals from other surgeons (rate ratio, 1.14; 95% CI, 1.13-1.16). Female physicians had a 1.6% (95% CI, 1.4%-1.9%) greater odds of same-sex referrals, whereas male physicians had a 32.0% (95% CI, 31.8%-32.2%) greater odds of same-sex referrals; differences did not attenuate over time.Conclusions and relevanceIn this cross-sectional, population-based study, male physicians appeared to have referral preferences for male surgeons; this disparity is not narrowing over time or as more women enter surgery. Such preferences lead to lower volumes of and fewer operative referrals to female surgeons and are associated with sex-based inequities in medicine.

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Deletion of Wt1 during early gonadogenesis leads to differences of sex development in male and female adult mice.

Publications

Deletion of Wt1 during early gonadogenesis leads to differences of sex development in male and female adult mice.

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