The putative forkhead transcription factor FOXL2 is mutated in blepharophimosis/ptosis/epicanthus inversus syndrome

Crisponi, Laura; Deiana, Manila; Loi, Alfredo; Chiappe, Francesca; Uda, Manuela; Amati, Patrizia; Bisceglia, Luigi; Zelante, Leopoldo; Nagaraja, Ramaiah; Porcu, Susanna; Ristaldi, Maria Serafina; Marzella, R.; Rocchi, Mariano; Nicolino, Marc; Lienhardt-Roussie, Anne; Nivelon, A; Verloes, Alain; Schlessinger, David; Gasparini, Paolo; Bonneau, Dominique; A, Cao; Pilia, Giuseppe

doi:10.1038/84781

Cited by 880 publications

(726 citation statements)

References 45 publications

Supporting

Mentioning

696

Contrasting

Unclassified

Order By: Relevance

“…It was generally believed that mouse eyelid formation starts at E13 (Crisponi et al, 2001;Findlater et Juriloff et al, 2000). This is perhaps because the protruding ridges become apparent during this stage of development.…”

Section: Discussionmentioning

confidence: 99%

“…It was recently reported that mutations leading to truncation of FOXL2, a putative forkhead transcription factor, results in an autosomal dominant disorder, blepharophimosis/ptosis/epicanthus inversus syndrome (BPES). BPES patients exhibit eyelid abnormalities characterized by small palpebral fissures, drooping eyelids, and a tiny skin fold running inward and upward from the lower lid (Crisponi et al, 2001). As no homozygous patients have been reported, it is impossible to predict the appearance of homozygous eyelids.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Fibroblast growth factor receptor 2 (Fgfr2) plays an important role in eyelid and skin formation and patterning

Guo

et al. 2001

Developmental Dynamics

View full text Add to dashboard Cite

Initiating as protruding ridges above and below the optic vesicle, the eyelids of mice grow across the eye and temporarily fuse in fetal life. Mutations of a number of genes disrupt this developmental process and result in a birth defect, "open-eyelids at birth." Here we show that a critical event for eyelid induction occurs at embryonic day 11.5 (E11.5) when the single cell-layered ectoderm in the presumptive eyelid territory increases proliferation and undergoes morphologic transition to form cube-shaped epithelial cells. Using embryos lacking the Fgfr2 Ig domain III (Fgfr2 ⌬III/⌬III ) generated by tetraploid rescue and chimeric embryo formation approaches, we demonstrate that this event is controlled by Fgfr2 signals as the Fgfr2 ⌬III/⌬III mutation blocks these changes and results in embryos without eyelids. Fgfr2 and its ligands are differentially expressed in the ectoderm and underlying mesenchyme and function in a reciprocal interacting loop that specifies eyelid development. We also demonstrate that similar defects account for failure of skin formation at early stages. Interestingly, Fgfr2-independent skin formation occurs at E14.5 mutant embryos, resulting in much thinner, yet well-differentiated epidermis. Notably, mutant skin remains thin with decreased hair density after transplantation to wild-type recipients. These data demonstrate an essential role of Fgfr2 in eyelid and skin formation and patterning. Published 2001 Wiley-Liss, Inc. †

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Fibroblast growth factor receptor 2 (Fgfr2) plays an important role in eyelid and skin formation and patterning

Guo

et al. 2001

Developmental Dynamics

View full text Add to dashboard Cite

show abstract

“…Mutations in FOXL2 cause blepharophimosis, ptosis, epicanthus inversus syndrome (OMIM #110100), and blepharophimosis, ptosis, epicanthus inversus syndrome type I is accompanied by premature ovarian failure of the affected female (Crisponi et al, 2001). FOXL2 is mainly expressed in undifferentiated granulosa cells, and blockage of ovarian follicle development because of the failure of granulosa cell differentiation was observed in FoxL2 lacZ homozygous mutant mice (Pisarska et al, 2004;Uda et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Differential apoptotic activities of wild-type FOXL2 and the adult-type granulosa cell tumor-associated mutant FOXL2 (C134W)

et al. 2010

View full text Add to dashboard Cite

Some mutations in FOXL2 result in premature ovarian failure accompanied by blepharophimosis, ptosis, epicanthus inversus syndrome type I disease, and FOXL2-null mice exhibit developmental defects in granulosa cells. Recently, FOXL2 c.402C4G, a new somatic mutation that leads to a p.C134W change, was found in the majority of adult-type ovarian granulosa cell tumors (GCTs). In this study, we investigated the possible mechanisms by which the C134W mutation contributes to the development of GCTs. Wild-type (WT) and mutant FOXL2 displayed differential apoptotic activities. Specifically, WT FOXL2 induced significant granulosa cell death, but the mutant exhibited minimal cell death. The FOXL2-induced apoptotic response was greatly dependent on caspase 8, BID and BAK because the depletion of any of these three proteins inhibited FOXL2 from eliciting the full apoptotic response. Activation of caspase 8 and subsequent increased production of truncated BID, and oligomerization of BAK, and release of cytochrome c were all associated with the apoptosis induced by WT FOXL2 expression. In contrast, the mutant FOXL2 was unable to elicit the full array of apoptotic signaling responses. In addition, we found differential TNF-R1 (tumor necrosis factor-receptor 1) and Fas (CD95/APO-1) upregulation between the WT and the mutant, and the silencing of TNF-R1 or Fas and the blockage of the death signaling mediated by TNF-R1 or Fas using TNF-Fc or Fas-Fc, respectively, resulted in significant attenuations of FOXL2-induced apoptosis. Moreover, granulosa cells that expressed either WT FOXL2 or mutant exhibited distinct cell death sensitivities on activation of death receptors and deprivation of serum. Thus, the differential activities of FOXL2 and its mutant may partially account for the pathophysiology of GCT development.

show abstract

“…Moreover, forkhead domain genes were found to be affected in tumorigenesis and in several human congenital syndromes (Li and Vogt, 1993;Barr, 1997;Chatila et al, 2000;Crisponi et al, 2001;Karkkainen et al, 2001;Lai et al, 2001;Wildin et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Survey of forkhead domain encoding genes in the Drosophila genome: Classification and embryonic expression patterns

Lee

Frasch

2004

Developmental Dynamics

View full text Add to dashboard Cite

Genetic approaches in Drosophila led to the identification of Forkhead, the prototype of forkhead domain transcription factors that are now known to comprise an evolutionarily conserved family of proteins with essential roles in development and differentiation. Sequence analysis of the recently published genomic scaffold sequence from Drosophila melanogaster has allowed us to determine the presumably full complement of forkhead domain encoding genes in this species. We show herein that the Drosophila genome contains 17 forkhead domain encoding genes; 13 of these genes have orthologs in chordate species, and their products can be assigned to 10 of the 17 forkhead domain subclasses known from chordates. One Drosophila forkhead domain gene only has a Caenorhabditis elegans ortholog and may represent a subclass that is absent in chordates, while the remaining three cannot be classified. We present the mRNA expression patterns of seven previously uncharacterized members of this gene family and show that they are expressed in tissues from all three germ layers, including central and peripheral nervous system, epidermis, salivary gland primordia, endoderm, somatic mesoderm, and hemocyte progenitors. Furthermore, the expression patterns of two of these genes, fd19B and fd102C, suggest a role for them as gap genes during early embryonic head segmentation.

show abstract

The putative forkhead transcription factor FOXL2 is mutated in blepharophimosis/ptosis/epicanthus inversus syndrome

Cited by 880 publications

References 45 publications

Fibroblast growth factor receptor 2 (Fgfr2) plays an important role in eyelid and skin formation and patterning

Fibroblast growth factor receptor 2 (Fgfr2) plays an important role in eyelid and skin formation and patterning

Differential apoptotic activities of wild-type FOXL2 and the adult-type granulosa cell tumor-associated mutant FOXL2 (C134W)

Survey of forkhead domain encoding genes in the Drosophila genome: Classification and embryonic expression patterns

Contact Info

Product

Resources

About