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早期性腺发生过程中 Wt1 的缺失导致雌雄成年小鼠的性别发育出现差异。

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

机构信息

Celltec-UB, Department of Cell Biology, Physiology and Immunology, Faculty of Biology, University of Barcelona, Barcelona, Spain.

Institute of Biomedicine (IBUB), University of Barcelona, Barcelona, Spain.

出版信息

PLoS Genet. 2022 Jun 15;18(6):e1010240. doi: 10.1371/journal.pgen.1010240. eCollection 2022 Jun.

DOI:10.1371/journal.pgen.1010240
PMID:35704566
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9200307/
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.

摘要

评估 WT1 转录因子（WT1）在早期性腺分化中的作用及其对成年性别发育的影响一直很困难，因为 Wt1KO 小鼠模型表现出完全的性腺发育不全和胚胎致死性。在这里，我们生成了 Wt1LoxP/GFP;Wt1Cre 小鼠，这是第一个在早期性腺发生过程中 WT1 表达显著降低而达到成年期的 Wt1KO 小鼠模型。Wt1LoxP/GFP;Wt1Cre 小鼠缺乏成熟的性腺，并表现出包含男性和女性生殖器结构以及两性生殖器的生殖器道。我们发现 WT1 对于激活男性和女性性别决定途径都是必需的，因为胚胎突变性腺未能上调每个遗传程序特异性基因的表达。Wt1LoxP/GFP;Wt1Cre 小鼠的性腺表现出缺乏 Sertoli 和前颗粒细胞的产生以及生殖细胞数量减少。NR5A1 和类固醇生成基因的表达在 XY 和 XX Wt1LoxP/GFP;Wt1Cre 性腺中以不同的方式调节，解释了突变表型。对 XX Wt1LoxP/GFP;Wt1Cre 性腺的进一步研究表明，WT1 的早期缺失会损害包括体细胞和卵巢上皮在内的几种细胞类型的分化。通过对这种 Wt1KO 小鼠模型的特征描述，我们表明在早期性腺发生过程中 WT1 的缺失会导致成年性别发育的严重缺陷。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2514/9200307/19ceeac766cd/pgen.1010240.g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2514/9200307/ce6582875714/pgen.1010240.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2514/9200307/5e3264a71a78/pgen.1010240.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2514/9200307/e116ee38ed2e/pgen.1010240.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2514/9200307/19ceeac766cd/pgen.1010240.g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2514/9200307/ce6582875714/pgen.1010240.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2514/9200307/5e3264a71a78/pgen.1010240.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2514/9200307/e116ee38ed2e/pgen.1010240.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2514/9200307/19ceeac766cd/pgen.1010240.g008.jpg

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Two distinct pathways of pregranulosa cell differentiation support follicle formation in the mouse ovary.
两种不同的颗粒细胞分化途径支持小鼠卵巢滤泡的形成。
Proc Natl Acad Sci U S A. 2020 Aug 18;117(33):20015-20026. doi: 10.1073/pnas.2005570117. Epub 2020 Aug 5.
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Retinoic acid synthesis by ALDH1A proteins is dispensable for meiosis initiation in the mouse fetal ovary.ALDH1A 蛋白合成视黄酸对于小鼠胎儿卵巢减数分裂起始并非必需。
Sci Adv. 2020 May 22;6(21):eaaz1261. doi: 10.1126/sciadv.aaz1261. eCollection 2020 May.
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