title: Novel action of FOXL2 as mediator of Col1a2 gene autoregulation.
abstract: FOXL2 belongs to the evolutionarily conserved forkhead box (FOX) superfamily and is a master transcription factor in a spectrum of developmental pathways, including ovarian and eyelid development and bone, cartilage and uterine maturation. To analyse its action, we searched for proteins that interact with FOXL2. We found that FOXL2 interacts with specific C-terminal propeptides of several fibrillary collagens. Because these propeptides can participate in feedback regulation of collagen biosynthesis, we inferred that FOXL2 could thereby affect the transcription of the cognate collagen genes. Focusing on COL1A2, we found that FOXL2 indeed affects collagen synthesis, by binding to a DNA response element located about 65Kb upstream of this gene. According to our hypothesis we found that in Foxl2(-/-) mouse ovaries, Col1a2 was elevated from birth to adulthood. The extracellular matrix (ECM) compartmentalizes the ovary during folliculogenesis, (with type I, type III and type IV collagens as primary components), and ECM composition changes during the reproductive lifespan. In Foxl2(-/-) mouse ovaries, in addition to up-regulation of Col1a2, Col3a1, Col4a1 and fibronectin were also upregulated, while laminin expression was reduced. Thus, by regulating levels of extracellular matrix components, FOXL2 may contribute to both ovarian histogenesis and the fibrosis attendant on depletion of the follicle reserve during reproductive aging and menopause.
authors.affiliation: Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Monserrato 09042, Italy.
authors.forename: Mara
authors.initials: M
authors.lastname: Marongiu
authors.affiliation: Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Monserrato 09042, Italy.
authors.forename: Manila
authors.initials: M
authors.lastname: Deiana
authors.affiliation: Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Monserrato 09042, Italy; Università degli Studi di Sassari, Sassari 07100, Italy.
authors.forename: Loredana
authors.initials: L
authors.lastname: Marcia
authors.affiliation: Centre for Advanced Studies, Research and Development in Sardinia (CRS4), Pula, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Sbardellati
authors.affiliation: Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Monserrato 09042, Italy.
authors.forename: Isadora
authors.initials: I
authors.lastname: Asunis
authors.affiliation: Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Monserrato 09042, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Meloni
authors.affiliation: Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Monserrato 09042, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Angius
authors.affiliation: Centre for Advanced Studies, Research and Development in Sardinia (CRS4), Pula, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Cusano
authors.affiliation: Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Monserrato 09042, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Loi
authors.affiliation: Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Monserrato 09042, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Crobu
authors.affiliation: Centre for Advanced Studies, Research and Development in Sardinia (CRS4), Pula, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Fotia
authors.affiliation: Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Monserrato 09042, Italy; Università degli Studi di Sassari, Sassari 07100, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Cucca
authors.affiliation: Laboratory of Genetics, NIA-IRP, NIH, Baltimore, 21224-6825 MD, United States.
authors.forename: David
authors.initials: D
authors.lastname: Schlessinger
authors.affiliation: Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Monserrato 09042, Italy. Electronic address: laura.crisponi@irgb.cnr.it.
authors.forename: Laura
authors.initials: L
authors.lastname: Crisponi
mesh_terms: D000818:Animals; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D024042:Collagen Type I / Q000235:genetics* / Q000378:metabolism; D016384:Consensus Sequence; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D000074842:Forkhead Box Protein L2; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D051379:Mice; D008810:Mice, Inbred C57BL; D020411:Oligonucleotide Array Sequence Analysis; D010053:Ovary / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding
chemical_list: C000619309:Col1a2 protein, mouse; D024042:Collagen Type I; D000074842:Forkhead Box Protein L2; D051858:Forkhead Transcription Factors; C498893:Foxl2 protein, mouse
keywords: COL1A2; ECM; FOXL2; Ovary; Transcriptional regulation