COUP-TFII is required for morphogenesis of the neural crest-derived tympanic ring

Hsu, Wen-Hwei; Chen, Chun Ming; You, Li Ru

doi:10.1038/s41598-017-12665-0

Cited by 10 publications

(9 citation statements)

References 65 publications

(72 reference statements)

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“…Single Nr2f1 mutants die perinatally without overt craniofacial abnormalities (Qiu et al, 1997), while Nr2f2 mouse mutants die with angiogenic and cardiac defects by E10.5 (Pereira et al, 1999). A recent study has shown that conditional mutation of Nr2f2 within NCCs results in ectopic Sox9 expression and abnormalities in the tympanic ring (Hsu et al, 2017), a proximal first arch-derived dermal bone (Mallo, 2001, Hsu et al, 2017), consistent with our finding that Nr2fs inhibit maxillary sox9a expression in fish. Deletions spanning the NR2F1 and NR2F2 genomic loci have also been identified in isolated human patients with craniofacial anomalies (Poot et al, 2007, Brown et al, 2009).…”

Section: Discussionsupporting

confidence: 92%

Essential Role of Nr2f Nuclear Receptors in Patterning the Vertebrate Upper Jaw

et al. 2018

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The jaw is central to the extensive variety of feeding and predatory behaviors across vertebrates. The bones of the lower but not upper jaw form around an early-developing cartilage template. Whereas Endothelin1 patterns the lower jaw, the factors that specify upper-jaw morphology remain elusive. Here, we identify Nuclear Receptor 2f genes (Nr2fs) as enriched in and required for upper-jaw formation in zebrafish. Combinatorial loss of Nr2fs transforms maxillary components of the upper jaw into lower-jaw-like structures. Conversely, nr2f5 misexpression disrupts lower-jaw development. Genome-wide analyses reveal that Nr2fs repress mandibular gene expression and early chondrogenesis in maxillary precursors. Rescue of lower-jaw defects in endothelin1 mutants by reducing Nr2f dosage further demonstrates that Nr2f expression must be suppressed for normal lower-jaw development. We propose that Nr2fs shape the upper jaw by protecting maxillary progenitors from early chondrogenesis, thus preserving cells for later osteogenesis.

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Section: Discussionsupporting

confidence: 92%

Essential Role of Nr2f Nuclear Receptors in Patterning the Vertebrate Upper Jaw

et al. 2018

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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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“…For example, in the human endometrium, COUP-TF2 is a positive regulator of the pro-ovary WNT4 gene and in mice Coup-tf2 negatively regulates the expression of the pro-testis Sox9 gene in the osteogenic mesenchyme. 29,30 In addition to revealing unforeseen mechanisms in sex development, our study also highlights the importance of nuclear receptors (NR) in human development and disease. Humans have 48 different NRs with a diverse range of functions and next-generation sequencing approaches are starting to identify novel and sometimes unexpected phenotypes associated with specific NR variants.…”

mentioning

confidence: 80%

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

Bashamboo¹,

Eozénou²,

Jørgensen³

et al. 2018

ESPE

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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 ¼ 2.44 3 10 À8). 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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COUP-TFII is required for morphogenesis of the neural crest-derived tympanic ring

Cited by 10 publications

References 65 publications

Essential Role of Nr2f Nuclear Receptors in Patterning the Vertebrate Upper Jaw

Essential Role of Nr2f Nuclear Receptors in Patterning the Vertebrate Upper Jaw

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

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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