Biological effects of FoxJ2 over-expression

Abstract

As reported previously, we have extensively studied FoxJ2, a member of the Fork Head transcription factors family. While the biochemical and functional structures of this transcription factor are well understood, its biological function remains unknown. Here, we present data that address this point using transgenic mouse technology. We found that the birth rate and the number of transgenic animals obtained when transferring embryos over-expressing the FoxJ2 protein were lower than those obtained with embryos over-expressing a control protein, suggesting FoxJ2 overexpression has a negative effect on embryonic development. Transient FoxJ2 transgenesis experiments have confirmed that FoxJ2 over-expression has a lethal effect on embryonic development from E10.5. Moreover, in vitro culture of FoxJ2-microinjected embryos demonstrated a significant developmental blockage, indicating that FoxJ2 could also have an effect on preimplantation stages. Most probably, these negative effects of FoxJ2 over-expression during development also explain the low percentage of adult transgenic mice obtained. Furthermore, most of the transgenic mice that lived to adulthood did not show transgene expression. In fact, the only two adult transgenic animals (one male and one female) in which FoxJ2 transgene expression was detected showed a mosaic expression and died prematurely as a result of cardio-respiratory failure. Postmortem analysis of these animals revealed a hypertrophic heart and abnormal testes in the male. In order to identify genes regulated by FoxJ2 consistent with the phenotypes observed for FoxJ2 transgenic mice, EMSA assays and co-transfection experiments were carried out. Our data indicate that the genes coding for the gap junction protein Connexin-43 and the cellcell contact protein E-Cadherin, may be good candidates for FoxJ2-regulated genes. Interestingly, Connexin-43 and E-Cadherin show expression patterns similar to FoxJ2, and the phenotypes of Connexin-43 and E-Cadherin mutants resemble those of our FoxJ2 transgenic animals. These data suggest that the lethal effect on embryonic development of FoxJ2 overexpression, as well as the alterations observed in the heart and testes of adult transgenic mice, could be determined by changes in the transcription of genes such as Connexin-43 and/or E-Cadherin.

The role of FoxJ2 in the migration of human glioma cells

“…Four regions of the molecule are essential for FoxJ2 to activate transcription: three transactivation domains, located on both sides of the Fork Head domain, and a proline/glutamine-rich region; the latter appears to be required for the full activity of the other domains, although it lacks transactivation capacity by itself alone. Previous reports have shown X. Qiu et al / Pathology -Research and Practice xxx (2015) xxx-xxx that the effects of overexpression of FoxJ2 could be mediated by a deregulation of the expression of genes such Cx-43 and E-Cad [21]. Many studies showed that Fox family genes play important roles in tumor cells dissemination [12,[22][23][24].…”

In Vitro Fertilization and Embryo Culture Strongly Impact the Placental Transcriptome in the Mouse Model

“…Furthermore, we showed that FoxJ2 was also up-regulated in IVF samples. FoxJ2 over-expression using transgenic mice has a negative effect on embryonic development [62].…”

MicroRNAs as regulators and mediators of forkhead box transcription factors function in human cancers

“…FOXJ2 protein is able to bind to the E-cadherin promoter and induce its expression in human hepatoma, breast cancer and cervix carcinoma [167, 168]. miR-34a is implicated in cell differentiation pathways from stem cell and precursor populations [169].…”