The genetic make‐up of ovarian development and function: the focus on the transcription factor <scp>FOXL2</scp>

Elzaïat, Maëva; Todeschini, Anne‐Laure; Caburet, Sandrine; Veitia, Reiner A.

doi:10.1111/cge.12862

Cited by 50 publications

(30 citation statements)

References 128 publications

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“…Forkhead box L2 (FOXL2, OMIM: 605597) is a forkhead transcription factor that contains a fork-head DNA-binding domain and plays a role in ovarian development and function [ 28 , 29 ]. Mutations in FOXL2 are known to cause autosomal dominant POI [ 30 – 34 ].…”

Section: Discussionmentioning

confidence: 99%

Whole-exome sequencing in patients with premature ovarian insufficiency: early detection and early intervention

et al. 2020

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Background The loss of ovarian function in women, referred to as premature ovarian insufficiency (POI), is associated with a series of concomitant diseases. POI is genetically heterogeneous, and in most cases, the etiology is unknown. Methods Whole-exome sequencing (WES) was performed on DNA samples obtained from patients with POI, and Sanger sequencing was used to validate the detected potentially pathogenic variants. An in silico analysis was carried out to predict the pathogenicity of the variants. Results We recruited 24 patients with POI and identified variants in POI-related genes in 14 patients, including bi-allelic mutations in DNAH6, HFM1, EIF2B2, BNC, and LRPPRC and heterozygous variants in BNC1, EIF2B4, FOXL2, MCM9, FANCA, ATM, EIF2B3, and GHR. No variants in the above genes were detected in the WES data obtained from 29 women in a control group without POI. Determining a clear genetic etiology could significantly increase patient compliance with appropriate intervention strategies. Conclusions Our study confirmed that POI is a genetically heterogeneous condition and that whole-exome sequencing is a powerful tool for determining its genetic etiology. The results of this study will aid researchers and clinicians in genetic counseling and suggests the potential of WES for the detection of POI and thus early interventions for patients with POI.

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Section: Discussionmentioning

confidence: 99%

Whole-exome sequencing in patients with premature ovarian insufficiency: early detection and early intervention

et al. 2020

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“…The forkhead transcription factor FOXL2 has been established as a master gene for folliculogenesis and maintenance of ovarian function in vertebrates [ 45 , 60 ]. Our previous data have shown that FOXL2 transcript and protein are expressed in bovine and ovine endometrium and are regulated by progesterone but not by oestradiol [ 28 , 61 ].…”

Section: Discussionmentioning

confidence: 99%

Maternal metabolism affects endometrial expression of oxidative stress and FOXL2 genes in cattle

et al. 2017

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Intensive selection for milk production has led to reduced reproductive efficiency in high-producing dairy cattle. The impact of intensive milk production on oocyte quality as well as early embryo development has been established but few analyses have addressed this question at the initiation of implantation, a critical milestone ensuring a successful pregnancy and normal post-natal development. Our study aimed to determine if contrasted maternal metabolism affects the previously described sensory properties of the endometrium to the conceptus in cattle. Following embryo transfer at Day 7 post-oestrus, endometrial caruncular (CAR) and intercaruncular (ICAR) areas were collected at Day 19 from primiparous postpartum Holstein-Friesian cows that were dried-off immediately after parturition (i.e., never milked; DRY) or milked twice daily (LACT). Gene quantification indicated no significant impact of lactation on endometrial expression of transcripts previously reported as conceptus-regulated (PLET1, PTGS2, SOCS6) and interferon-tau stimulated (RSAD2, SOCS1, SOCS3, STAT1) factors or known as female hormone-regulated genes (FOXL2, SCARA5, PTGS2). Compared with LACT cows, DRY cows exhibited mRNA levels with increased expression for FOXL2 transcription factor and decreased expression for oxidative stress-related genes (CAT, SOD1, SOD2). In vivo and in vitro experiments highlighted that neither interferon-tau nor FOXL2 were involved in transcriptional regulation of CAT, SOD1 and SOD2. In addition, our data showed that variations in maternal metabolism had a higher impact on gene expression in ICAR areas. Collectively, our findings prompt the need to fully understand the extent to which modifications in endometrial physiology drive the trajectory of conceptus development from implantation onwards when maternal metabolism is altered.

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“…Goat XX fetuses lacking Foxl2 have gonads resembling testes and the induced absence of Foxl2 in adult XX mice results in trans -differentiation of the ovaries into a testis-like gonad. 9 , 10 , 11 In humans, heterozygous loss-of-function FOXL2 mutations are associated with autosomal-dominant blepharophimosis-ptosis-epicanthus inversus syndrome (BPES [MIM: 110100 ]) either with (type I) or without (type 2) ovarian insufficiency as well as ovarian insufficiency without BPES (MIM: 608996 ), but homozygous FOXL2 disruption has not been described. 10 The limited understanding of the genes involved in ovary formation means that for most children with OTDSD/TDSD, the molecular basis is currently unknown.…”

Section: Main Textmentioning

confidence: 99%

Loss of Function of the Nuclear Receptor NR2F2, Encoding COUP-TF2, Causes Testis Development and Cardiac Defects in 46,XX Children

Bashamboo

Eozénou

Jørgensen

et al. 2018

The American Journal of Human Genetics

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Emerging evidence from murine studies suggests that mammalian sex determination is the outcome of an imbalance between mutually antagonistic male and female regulatory networks that canalize development down one pathway while actively repressing the other. However, in contrast to testis formation, the gene regulatory pathways governing mammalian ovary development have remained elusive. We performed exome or Sanger sequencing on 79 46,XX SRY-negative individuals with either unexplained virilization or with testicular/ovotesticular disorders/differences of sex development (TDSD/OTDSD). We identified heterozygous frameshift mutations in NR2F2, encoding COUP-TF2, in three children. One carried a c.103_109delGGCGCCC (p.Gly35Argfs∗75) mutation, while two others carried a c.97_103delCCGCCCG (p.Pro33Alafs∗77) mutation. In two of three children the mutation was de novo. All three children presented with congenital heart disease (CHD), one child with congenital diaphragmatic hernia (CDH), and two children with blepharophimosis-ptosis-epicanthus inversus syndrome (BPES). The three children had androgen production, virilization of external genitalia, and biochemical or histological evidence of testicular tissue. We demonstrate a highly significant association between the NR2F2 loss-of-function mutations and this syndromic form of DSD (p = 2.44 × 10−8). We show that COUP-TF2 is highly abundant in a FOXL2-negative stromal cell population of the fetal human ovary. In contrast to the mouse, these data establish COUP-TF2 as a human “pro-ovary” and “anti-testis” sex-determining factor in female gonads. Furthermore, the data presented here provide additional evidence of the emerging importance of nuclear receptors in establishing human ovarian identity and indicate that nuclear receptors may have divergent functions in mouse and human biology.

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The genetic make‐up of ovarian development and function: the focus on the transcription factor FOXL2

Cited by 50 publications

References 128 publications

Whole-exome sequencing in patients with premature ovarian insufficiency: early detection and early intervention

Whole-exome sequencing in patients with premature ovarian insufficiency: early detection and early intervention

Maternal metabolism affects endometrial expression of oxidative stress and FOXL2 genes in cattle

Loss of Function of the Nuclear Receptor NR2F2, Encoding COUP-TF2, Causes Testis Development and Cardiac Defects in 46,XX Children

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