大畑 慎也

<title>Abstract</title> The fusion protein of uncharacterised zinc finger translocation associated (ZFTA) and effector transcription factor of tumorigenic NF-kB 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.

Mice lacking the stress-signaling kinases SEK1 and MKK7 die from embryonic day 10.5 (E10.5) to E12.5 with a defect in liver formation. However, the mechanism of the liver defect has remained unknown. In this review, we first introduce a monoclonal antibody, anti-Liv2, which specifically recognizes murine hepatoblasts, for the analysis of liver development, and further, we describe the genetic interaction of sek1 with the tumor necrosis factor-alpha receptor 1 gene (tnfr1) and the protooncogene c-jun, which are also responsible for liver formation and cell apoptosis. The defective liver formation in sek1(-/-) embryos was not protected by an additional tufr1 mutation that rescues the embryonic lethality of mice lacking nuclear factor-kappa B (NF-kappaB) signaling components. There was a progressive increase in hepatoblast cell numbers in wild-type embryos from E10.5 to E12.5. In contrast, impaired hepatoblast proliferation was observed in sek1(-/-) livers from E10.5, although fetal liver-specific gene expression was normal. The impaired phenotype in sek1(-/-) livers was more severe than that in c-jun(-/-) embryos, and sek1(-/-) c-jun(-/-) embryos died earlier before E8.5. The hepatoblast proliferation required no hematopoiesis, because liver development was not impaired in AML1(-/-) mice, which lack hematopoietic functions. Stimulation of stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) by hepatocyte growth factor was attenuated in sek1(-/-) livers. Thus, SEK1 and MKK7-mediated SAPK/JNK signaling appears to play a crucial role in hepatoblast proliferation and survival in a manner that is apparently different from that of NF-kappaB or c-jun.