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.

Collagen (I) homotrimer potentiates the osteogenesis imperfecta (oim) mutant allele and reduces survival in male mice

“…The genetic interaction between the oim allele and homotrimeric collagen (I) could relate to the process of collagen folding and trimerization within the endoplasmic reticulum, or indeed the homotrimeric collagen (I) could alter cellmatrix interactions to modulate cellular stress responses. Procollagen N and Cpropeptides, derived from the proteolytic cleavage of procollagen, have been shown to have intracellular roles in modulating protein synthesis (Hayata et al, 2008;Marongiu et al, 2016;Oganesian et al, 2006) whilst homotrimeric triple helical regions increased proliferation and migration as compared to heterotrimeric pepsinised collagen (Makareeva et al, 2010). Hence homotrimeric forms of collagen fibrils or propeptides have the potential for altered signalling affecting cellular stress responses.…”

“…Alternatively the homotrimeric collagen (I) could alter cell-matrix interactions to modulate cellular stress responses, if present. Procollagen N-and Cpropeptides, derived from the proteolytic cleavage of procollagen, have been shown to have intracellular roles in modulating protein synthesis (56)(57)(58) whilst homotrimeric triple helical regions increased proliferation and migration as compared to heterotrimeric pepsinised collagen (11). Hence homotrimeric forms of collagen fibrils or propeptides have the potential for altered signalling affecting cellular stress responses.…”

Fine mapping of goat polledness variant in six Chinese native breeds

“…We also found that ERG-targeted genes, like IGF2 and IGFBP1 [21] were upregulated, while some interactive genes, such as homeobox genes, Hoxc6, 8, 9, 5, and Hoxb7, 6, 3, as well as Hoxa9, 7 [22][23][24] were downregulated in horn bud tissues of polled goats (Additional file 3: Table S1). In addition, FOXL2-regulated genes, such as some collagen genes [25] , were upregulated in the horn bud tissues of polled goats too (Additional file 3: Table S1). pairwise comparison between horn bud and skin of polled and horned goats, as well as between horn bud of horned and polled goats.…”

FOXO1 mitigates the SMAD3/FOXL2C134W transcriptomic effect in a model of human adult granulosa cell tumor

“…Potential FOXL2 targets revealed by ChIP and RT-PCR implicated its involvement in follicular and craniofacial development [ 18 – 20 ]. It has been also shown that FOXL2 affects collagen synthesis [ 21 , 22 ]. Nicol et al .…”