Abstract
BackgroundHaploinsufficiency of the FOXL2 transcription factor in humans causes Blepharophimosis/Ptosis/Epicanthus Inversus syndrome (BPES), characterized by eyelid anomalies and premature ovarian failure. Mice lacking Foxl2 recapitulate human eyelid/forehead defects and undergo female gonadal dysgenesis. We report here that mice lacking Foxl2 also show defects in postnatal growth and embryonic bone and cartilage formation.MethodsFoxl2−/− male mice at different stages of development have been characterized and compared to wild type. Body length and weight were measured and growth curves were created. Skeletons were stained with alcian blue and/or alizarin red. Bone and cartilage formation was analyzed by Von Kossa staining and immunofluorescence using anti-FOXL2 and anti-SOX9 antibodies followed by confocal microscopy. Genes differentially expressed in skull vaults were evaluated by microarray analysis. Analysis of the GH/IGF1 pathway was done evaluating the expression of several hypothalamic-pituitary-bone axis markers by RT-qPCR.ResultsCompared to wild-type, Foxl2 null mice are smaller and show skeletal abnormalities and defects in cartilage and bone mineralization, with down-regulation of the GH/IGF1 axis. Consistent with these effects, we find FOXL2 expressed in embryos at 9.5 dpc in neural tube epithelium, in head mesenchyme near the neural tube, and within the first branchial arch; then, starting at 12.5 dpc, expressed in cartilaginous tissue; and at PO and P7, in hypothalamus.ConclusionsOur results support FOXL2 as a master transcription factor in a spectrum of developmental processes, including growth, cartilage and bone formation. Its action overlaps that of SOX9, though they are antagonistic in female vs male gonadal sex determination but conjoint in cartilage and skeletal development.Electronic supplementary materialThe online version of this article (doi:10.1186/s12861-015-0072-y) contains supplementary material, which is available to authorized users.
Highlights
Haploinsufficiency of the FOXL2 transcription factor in humans causes Blepharophimosis/Ptosis/ Epicanthus Inversus syndrome (BPES), characterized by eyelid anomalies and premature ovarian failure
To avoid possible additional effects of unbalanced female sex hormone levels on the phenotypes under study, we focused on Foxl2−/− males
The GH/Insulin-like growth factor 1 (IGF1) axis is impaired in Foxl2−/− mice Because IGF1 serum levels were lower in Foxl2−/−, we explored the possibility that aberrant growth in these mice could result from alteration of the GH/IGF1 axis [8]
Summary
Haploinsufficiency of the FOXL2 transcription factor in humans causes Blepharophimosis/Ptosis/ Epicanthus Inversus syndrome (BPES), characterized by eyelid anomalies and premature ovarian failure. Mice lacking Foxl recapitulate human eyelid/forehead defects and undergo female gonadal dysgenesis. We report here that mice lacking Foxl show defects in postnatal growth and embryonic bone and cartilage formation. Methods: Foxl2−/− male mice at different stages of development have been characterized and compared to wild type. Bone and cartilage formation was analyzed by Von Kossa staining and immunofluorescence using anti-FOXL2 and anti-SOX9 antibodies followed by confocal microscopy. FOXL2 (MIM #605597) was first implicated in human development as mutated in BPES (MIM #110100), an autosomal dominant disorder characterized by eyelid/ forehead anomalies associated with ovarian dysfunction leading to primary ovarian insufficiency [1,2,3]. Foxl is expressed in the gonadotropic cells of the pituitary gland at 11.5 dpc and in the thyrotropic and gonadotropic cells of the adult pituitary [10]; in the dorsal maxillary first branchial arch (BA1); and in a delimited domain at the maxillary-mandibular junction at 10.5 dpc [11]
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