318회 Signal Interactions and Transcriptional Regulations of BMP-4 duri…

318회

연사 : 김 재 봉 , 한림대학교 의과대학

제목:  Signal Interactions and Transcriptional Regulations of BMP-4 during the Early Development of Xenopus laevis

Abstract

  BMP-4 is a secreted factor regulating embryonic development and the proper regulation of the BMP-4 is critical to the dorsoventral specification of both mesoderm and ectoderm.  BMP-4 signaling is mediated through a set of evolutionary conserved family of Smad proteins which, upon activation, directly translocate to the nucleus where they may activate transcription. However, little is known about how BMP-4 signaling regulates the transcription of itself and its target genes, e.g. Xvent genes. In order to better understand the regulatory mechanisms occurring in nucleus, we isolated the genomic clones of a BMP-4 and BMP-4 responsive homeobox genes, Xbr-1a/Xvent-2 and P.V.1.  We characterized the BMP-4, Xbr-1a/Xvent-2 and P.V.1 genomic genes and investigated the regulation of their transcription during the early development of Xenopus embryos.  We found that repression of BMP-4 transcription is important in the maintenance of dorsal fate and that continuous input of BMP-4 signaling is required to sustain the expression of BMP-4 transcription in the maintenance of epidermal/ventral fate.  The serial deletion mutation of Xbr-1a/Xvent-2 promoter indicates that two separated 15 bp regions contain a strong positive element and the BMP-4/Smad1 response element.  Further analysis by site directed mutagenesis suggest that those two separated regions cooperate for the promoter activity and BMP-4 response.  In addition, we investigated the inhibitory roles of BMP-4/Smad1 signaling during the neurogenesis of prospective ectoderm, and signal interactions between Smad and FGF/Ras signaling during the early Xenopus development.  The receptor-activated Smads have recently been reported to cross-talk with other signals such as EGF, NGF, IFN-γ and Ras using mammalian cell lines.  In Xenopus embryonic system, BMP and activin have distinctive fate determination abilities in animal cap explants, i.e. ventral/epidermal and dorsal/neural respectively.  We used these fate determination abilities to test the roles of Smad 1 and 2 signal pathways, and the signal interactions with FGF signaling.  Our results suggested that FGF/Ras signal exibits dual effects, antagonizm with BMP-4/Smad1 signaling and synergism with activin/Smad-2 signaling during the early development of Xenopus embryos.