Abstract
The fusion protein of uncharacterised zinc finger translocation associated (ZFTA) and effector transcription factor of tumorigenic NF-κB signalling, RELA (ZFTA-RELA), is expressed in more than two-thirds of supratentorial ependymoma (ST-EPN-RELA), but ZFTA’s expression profile and functional analysis in multiciliated ependymal (E1) cells have not been examined. Here, we showed the mRNA expression of mouse Zfta peaks on embryonic day (E) 17.5 in the wholemount of the lateral walls of the lateral ventricle. Zfta was expressed in the nuclei of FoxJ1-positive immature E1 (pre-E1) cells in E18.5 mouse embryonic brain. Interestingly, the transcription factors promoting ciliogenesis (ciliary TFs) (e.g., multicilin) and ZFTA-RELA upregulated luciferase activity using a 5′ upstream sequence of ZFTA in cultured cells. Zftatm1/tm1 knock-in mice did not show developmental defects or abnormal fertility. In the Zftatm1/tm1 E1 cells, morphology, gene expression, ciliary beating frequency and ependymal flow were unaffected. These results suggest that Zfta is expressed in pre-E1 cells, possibly under the control of ciliary TFs, but is not essential for ependymal development or flow. This study sheds light on the mechanism of the ZFTA-RELA expression in the pathogenesis of ST-EPN-RELA: Ciliary TFs initiate ZFTA-RELA expression in pre-E1 cells, and ZFTA-RELA enhances its own expression using positive feedback.
Highlights
Ependymal (E1) cells are multiciliated epithelial cells that line the walls of the brain ventricles and help circulate the cerebrospinal fluid (CSF) through the beating of their motile cilia[1,2]
We found that the ependymoma-associated Zfta gene was expressed in positive immature E1 (pre-E1) cells, which are the source of ependymomas[10], possibly under the control of ciliary transcription factors (TFs) (Fig. 7Fa)
Since the expression of zinc finger translocation associated (ZFTA)-RELA fusion gene is likely regulated by the 5′ upstream sequence of ZFTA18, these TFs could be involved in the expression of oncogenic ZFTA-RELA in pre-E1 cells, potentially underlying the pathogenesis of STEPN-RELA
Summary
Ependymal (E1) cells are multiciliated epithelial cells that line the walls of the brain ventricles and help circulate the cerebrospinal fluid (CSF) through the beating of their motile cilia[1,2]. ZFTA forms fusion proteins with mastermind-like transcriptional coactivator 2 (MAML2), transcriptional activator MN1, nuclear receptor coactivator 1 and 2 (NCOA1/2) and Yes[1] associated transcriptional regulator (YAP1)[12,19,20,21] These fusion proteins are involved in the formation of other subtypes of ependymomas. Mouse models of ependymoma have been generated by the transplantation of ZFTA-RELA-expressing neural stem cells into adult mouse brain[12] and the exogenous expression of ZFTA-RELA in neonatal mouse brain[22,23]. Despite these reports, the expression profile and potential function of ZFTA in the development of E1 cells have yet to be elucidated. Inhibition of the ZFTA portion of ZFTA-RELA may be a therapeutic strategy for the brain tumours with poor prognoses
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